- CHEMICAL COMPOUNDS
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The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.
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Paragraph 0191-0193
(2021/04/02)
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- Synthesis of sp 3-Enriched β-Fluoro Sulfonyl Chlorides
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A three-step approach to the synthesis of sp 3-enriched β-fluoro sulfonyl chlorides starting from alkenes is reported. The method was successfully applied to a wide range of acyclic and cyclic substrates, bearing either an exocyclic or an endocyclic double bond. The procedure worked with a wide range of substrates and tolerated a number of functional and protecting groups. Moreover, the target cyclic compounds were obtained as single cis diastereomers on a multigram scale. The title compounds are promising building blocks for drug discovery that can be used to obtain sp 3-enriched β-fluoro and α,β-unsaturated sulfonamides.
- Gurbanov, Rustam,Sokolov, Andriy,Golovach, Sergey,Melnykov, Kostiantyn,Dobrydnev, Alexey V.,Grygorenko, Oleksandr O.
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p. 1771 - 1784
(2020/12/28)
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- Site-Specific Alkene Hydromethylation via Protonolysis of Titanacyclobutanes
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Methyl groups are ubiquitous in biologically active molecules. Thus, new tactics to introduce this alkyl fragment into polyfunctional structures are of significant interest. With this goal in mind, a direct method for the Markovnikov hydromethylation of alkenes is reported. This method exploits the degenerate metathesis reaction between the titanium methylidene unveiled from Cp2Ti(μ-Cl)(μ-CH2)AlMe2 (Tebbe's reagent) and unactivated alkenes. Protonolysis of the resulting titanacyclobutanes in situ effects hydromethylation in a chemo-, regio-, and site-selective manner. The broad utility of this method is demonstrated across a series of mono- and di-substituted alkenes containing pendant alcohols, ethers, amides, carbamates, and basic amines.
- Bartfield, Noah M.,Frederich, James H.,Law, James A.
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supporting information
p. 14360 - 14364
(2021/05/27)
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- Branch-Selective Addition of Unactivated Olefins into Imines and Aldehydes
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Radical hydrofunctionalization occurs with ease using metal-hydride hydrogen atom transfer (MHAT) catalysis to couple alkenes and competent radicalophilic electrophiles. Traditional two-electron electrophiles have remained unreactive. Herein we report the reductive coupling of electronically unbiased olefins with imines and aldehydes. Iron catalysis allows addition of alkyl-substituted olefins into imines through the intermediacy of free radicals, whereas a combination of catalytic Co(Salt-Bu,t-Bu) and chromium salts enables a branch-selective coupling of olefins and aldehydes through the formation of a putative alkyl chromium intermediate.
- Matos, Jeishla L. M.,Vásquez-Céspedes, Suhelen,Gu, Jieyu,Oguma, Takuya,Shenvi, Ryan A.
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supporting information
p. 16976 - 16981
(2019/01/04)
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- Hydrophilic azaspiroalkenes as robust bioorthogonal reporters
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Two hydrophilic spiroalkenes, azaspiro[2.3]hex-1-ene and azaspiro[2.4]hept-1-ene, were designed and synthesized. Compared to the previously reported spiro[2.3]hex-1-ene, the azaspiroalkenes exhibited greater water solubility and reactivity as dipolarophiles in the photoinduced tetrazole-alkene cycloaddition reaction. In addition, an azaspiro[2.3]hex-1-ene-containing amino acid, AsphK, was found to be charged by an engineered pyrrolysyl-tRNA synthetase into proteins via amber codon suppression in E. coli as well as in mammalian cells.
- An, Peng,Wu, Hsuan-Yi,Lewandowski, Tracey M.,Lin, Qing
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supporting information
p. 14005 - 14008
(2019/01/03)
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- Pleuromutilin antibiotics
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The present invention relates to pleuromutilin antibiotics represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R, R, R, R, m, X and Y are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and/or prevention of diseases caused by microorganisms.
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- Spiroisoxazoline Compounds Having an Activity Potentiating the Activity of an Antibiotic
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The present invention concerns a spiroisoxazoline compound of general formula (I): in which m and n are 0 or 1, R1 represents, inter alia, an optionally substituted alkyl chain, in particular substituted with fluorine or with a cyclic group, and R2 is chosen from phenyl and optionally substituted benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the heterocycles having 5 or 6 vertices comprising at least one atom chosen from S, N and O. The present invention also concerns the use of this compound as a drug, in particular in the treatment of bacterial and mycobacterial infections such as tuberculosis in combination with an antibiotic that is active against bacteria and/or mycobacteria, said compound potentiating the activity of said antibiotic.
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Paragraph 0053; 0054; 0056
(2015/12/23)
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- SELECTIVE OCTAHYDRO-CYCLOPENTA[C] PYRROLE NEGATIVE MODULATORS OF NR2B
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Compounds that selectively negatively modulate NMDA receptors containing an NR1/NR2B subunit, pharmaceutical compositions comprising the compounds, and methods of treating a disease using the compounds are disclosed. Such diseases include, without limitation, neurological dysfunction such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and seizure disorders; emotional disorders; depression; bipolar disorder; obsessive-compulsive disorder; and other anxiety disorders.
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Paragraph 0217
(2015/04/15)
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- AZAINDAZOLE COMPOUNDS AS INHIBITORS OF T790M CONTAINING EGFR MUTANTS
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This invention relates to novel compounds of formula (I), which are inhibitors of T790M containing EGFR mutants, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 138
(2015/01/16)
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- SPIRO AZETIDINE ISOXAZOLE DERIVATIVES AND THEIR USE AS SSTR5 ANTAGONISTS
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Provided is a compound represented by the following formula (1) or a salt thereof, which has an SSTR5 antagonistic action: wherein each symbol has the same definition as in the specification.
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Paragraph 0379; 1353; 1535
(2014/09/29)
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- Identification of false positives in hTS hits to lead : The application of Bayesian models in HTS triage to rapidly deliver a series of selective TRPV4 antagonists
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Herein, we describe the discovery and optimisation of a series of potent and selective TRPV4 antagonists. The application of a variety of computational techniques (including Bayesian modelling) at the HTS triage stage enabled the early deprioritisation of likely frequent hitters. The use of methods to positively prioritise compounds for follow-up screening allowed the rapid identification of a number of interesting TRPV4 antagonist series. The hit-to-lead efforts in one such series, the hydroxypiperidines, will be described. The Royal Society of Chemistry 2013.
- Skerratt, Sarah E.,Mills, James E. J.,Mistry, Jayesh
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p. 244 - 251
(2013/03/14)
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- CYTOMEGALOVIRUS INHIBITOR COMPOUNDS
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Compounds of Formula (I) wherein n, A, R1, R2, R3 and R5 are defined herein, are useful for the treatment of cytomegalovirus disease and/or infection.
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Page/Page column 30
(2013/10/22)
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- NAPHTHYRIDINONE DERIVATIVES AS INHIBITORS OF CYTOMEGALOVIRUS DNA POLYMERASE
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Compounds of Formula (I) wherein n, m, R1, R2, R3, R4, R5 and R6 are defined herein, are useful for the treatment of cytomegalovirus disease and/or infection.
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Page/Page column 26
(2013/10/22)
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- Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)
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The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
- Rice, Kenneth D.,Aay, Naing,Anand, Neel K.,Blazey, Charles M.,Bowles, Owen J.,Bussenius, Joerg,Costanzo, Simona,Curtis, Jeffry K.,Defina, Steven C.,Dubenko, Larisa,Engst, Stefan,Joshi, Anagha A.,Kennedy, Abigail R.,Kim, Angie I.,Koltun, Elena S.,Lougheed, Julie C.,Manalo, Jean-Claire L.,Martini, Jean-Francois,Nuss, John M.,Peto, Csaba J.,Tsang, Tsze H.,Yu, Peiwen,Johnston, Stuart
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supporting information; experimental part
p. 416 - 421
(2012/06/30)
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- NOVEL SPIROHETEROCYCLIC COMPOUNDS AS MGLU5 ANTAGONISTS
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The invention provides compounds having the general formula (I) wherein X is O or S; R1 is C, N, O or S; R1a is CH, CH2, N or NH; R2 is a bond, CH or CH2; m is 1, 2 or 3; n is 1 or 2; when n is 2 or m is 2 or 3, the ring containing R1 may be fused with a benzene ring; each --- represents a single or double bond provided that one double bond extends from the carbon atom to which R3-C≡C- is bonded and that no ring carbon atom bears two double bonds; and R3, R4 and R5 represent a wide range of substituents. These compounds are selective for the metabotropic mGlu5 receptor. They, their solvates, hydrates, enantiomers, diastereomers, N-oxides and pharmaceutically acceptable salts, and pharmaceutical compositions containing them, can be used to treat diseases or disorders of the lower urinary tract, especially neuromuscular dysfunctions of the lower urinary tract. They may also be useful for the treatment of migraine; for the treatment of gastroesophageal reflux disease (GERD); for the treatment of anxiety disorder; for the treatment of abuse, substance dependence and substance withdrawal disorder; for the treatment of neuropathic pain disorder; and for the treatment of fragile X syndrome disorders.
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Page/Page column 47-48
(2012/02/01)
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- TRIAZOLOPYRIDINE COMPOUNDS AS PIM KINASE INHIBITORS
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Compounds of Formula (I), in which A, B, R1, R1a, R2, R3, R4, R5, R6, and R7 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of immune cell-associated diseases and disorders, such as inflammatory and autoimmune diseases.
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Page/Page column 127; 128
(2010/04/03)
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- Synthesis of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate
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Image Persented Two efficient and scaleable synthetic routes to previously unknown bifunctional tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate are described. This compound and related intermediates described herein are useful for further selective derivation on the azetidine and cyclobutane rings providing a convenient entry point to novel compounds accessing chemical space complementary to piperidine ring systems.
- Meyers, Marvin J.,Muizebelt, Inouk,Van Wiltenburg, Jim,Brown, David L.,Thorarensen, Atli
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supporting information; experimental part
p. 3523 - 3525
(2011/02/22)
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- METHODS OF USING MEK INHIBITORS
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The present invention provides methods of treating cancer by administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments.
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Page/Page column 339-340
(2008/12/06)
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- METHODS OF USING COMBINATIONS OF MEK AND JAK-2 INHIBITORS
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A method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a MEK compound of Formula I(M), or a pharmaceutical composition comprising a therapeutically effective amount of a MEK compound of Formula I(M) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 compound of Formula I(J), or a pharmaceutical composition comprising a therapeutically effective amount of a JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, wherein the MEK compound of Formula I(M) and JAK-2 compound of Formula I(J) are as defined in the specification.
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Page/Page column 190
(2008/12/04)
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