- Cycloaddition Strategies for the Synthesis of Diverse Heterocyclic Spirocycles for Fragment-Based Drug Discovery
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In recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug
- King, Thomas A.,Stewart, Hannah L.,Mortensen, Kim T.,North, Andrew J. P.,Sore, Hannah F.,Spring, David R.
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- Intramolecular Ring-Opening Decomposition of Aryl Azetidines
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The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
- Bai, Guoyun,Brodney, Michael A.,Brown, Matthew F.,Butler, Christopher R.,Czabaniuk, Lara C.,Gilbert, Adam M.,Lachapelle, Erik A.,Li, Chao,McAllister, Laura A.,O'Connell, Thomas N.,Ogilvie, Kevin,Philippe, Laurence,Salomon-Ferrer, Romelia,Shapiro, Michael J.,Starr, Jeremy T.,Uccello, Daniel P.,Withka, Jane M.,Yan, Jiangli
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supporting information
p. 1585 - 1588
(2021/10/21)
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- Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
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A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
- Le Manach, Claire,Dam, Jean,Woodland, John G.,Kaur, Gurminder,Khonde, Lutete P.,Brunschwig, Christel,Njoroge, Mathew,Wicht, Kathryn J.,Horatscheck, André,Paquet, Tanya,Boyle, Grant A.,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Yeo, Tomas,Mok, Sachel,Eastman, Richard T.,Dorjsuren, Dorjbal,Talley, Daniel C.,Guo, Hui,Simeonov, Anton,Reader, Janette,Van Der Watt, Mari?tte,Erlank, Erica,Venter, Nelius,Zawada, Jacek W.,Aswat, Ayesha,Nardini, Luisa,Coetzer, Theresa L.,Lauterbach, Sonja B.,Bezuidenhout, Belinda C.,Theron, Anjo,Mancama, Dalu,Koekemoer, Lizette L.,Birkholtz, Lyn-Marie,Wittlin, Sergio,Delves, Michael,Ottilie, Sabine,Winzeler, Elizabeth A.,Smith, Dennis,Fidock, David A.,Street, Leslie J.,Basarab, Gregory S.,Duffy, James,Chibale, Kelly
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p. 2291 - 2309
(2021/03/01)
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- Monoprotected Diamines Derived from 1,5-Disubstituted (Aza)spiro[2.3]hexane Scaffolds
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Synthesis of monoprotected diamines derived from 1,5-disubstituted spiro[2.3]hexane and 5-azaspiro[2.3]hexane scaffolds is described. In both cases, the method relied on the cyclopropanation of the corresponding cyclobutane or azetidine derivatives. In th
- Malashchuk, Andrii,Chernykh, Anton V.,Perebyinis, Mariana Y.,Komarov, Igor V.,Grygorenko, Oleksandr O.
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p. 6570 - 6579
(2021/03/03)
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- Cobalt-Catalyzed Diastereo- And Enantioselective Reductive Allyl Additions to Aldehydes with Allylic Alcohol Derivatives via Allyl Radical Intermediates
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Catalytic generation of ambiphilic π-allyl-metal complexes and their utility in enantioselective transformations constitutes a powerful approach for introduction of allyl groups to a molecule. Herein an unprecedented cobalt-catalyzed highly site-, diastereo-, and enantioselective protocol for stereoselective formation of nucleophilic allyl-Co(II) complexes followed by addition to aldehydes is presented. The reaction features diastereo- and enantioconvergent conversion of easily accessible allylic alcohol derivatives to diversified enantioenriched homoallylic alcohols with a remarkably broad scope of allyl groups that can be introduced. Mechanistic studies indicated that allyl radical intermediates were involved in this process. These new discoveries establish a new strategy for development of enantioselective transformations through capture of radicals by chiral Co complexes, pushing forward the frontier of Co complexes for enantioselective catalysis.
- Wang, Lei,Wang, Lifan,Li, Mingxia,Chong, Qinglei,Meng, Fanke
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supporting information
p. 12755 - 12765
(2021/08/30)
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- QUINAZOLINE DERIVATIVES AS ANTITUMOR AGENTS
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The present application relates to novel quinazoline compounds as inhibitors of type I receptor tyrosine kinases, the pharmaceutical compositions comprising one or more of the compounds and salts thereof as an active ingredient, and the use of the compounds and salts thereof in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans.
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Page/Page column 166
(2020/04/25)
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- Synthesis of All-Carbon Quaternary Centers by Palladium-Catalyzed Olefin Dicarbofunctionalization
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The redox-neutral dicarbofunctionalization of tri- and tetrasubstituted olefins to form a variety of (hetero)cyclic compounds under photoinduced palladium catalysis is described. This cascade reaction process was used to couple styrenes or acryl amides with a broad range of highly decorated olefins tethered to aryl or alkyl bromides (>50 examples). This procedure enables one or two contiguous all-carbon quaternary centers to be formed in a single step. The products could be readily diversified and applied in the synthesis of a bioactive oxindole analogue.
- Koy, Maximilian,Bellotti, Peter,Katzenburg, Felix,Daniliuc, Constantin G.,Glorius, Frank
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supporting information
p. 2375 - 2379
(2020/01/24)
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- Rhodium catalyzed C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates and analogs
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The C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates with aryl boronic acids catalyzed by a rhodium complex was studied with a "conjugate addition/β-C cleavage/protonation" strategy.
- Yang, Xuan,Kong, Wei-Yu,Gao, Jia-Ni,Cheng, Li,Li, Nan-Nan,Li, Meng,Li, Hui-Ting,Fan, Jun,Gao, Jin-Ming,Ouyang, Qin,Xie, Jian-Bo
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supporting information
p. 12707 - 12710
(2019/10/28)
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- CARBOXAMIDES AS UBIQUITIN-SPECIFIC PROTEASE INHIBITORS
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The present disclosure relates to modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25, pharmaceutical compositions comprising the inhibitors, and methods of using the inhibitors. The modulators, such as inhibitors, of at least one pathway chosen from USP28 and USP25 can be useful in the treatment of cancers, among other ailments.
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Paragraph 00285
(2019/02/25)
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- 5,7-DIHYDRO-PYRROLO-PYRIDINE DERIVATIVES FOR TREATING NEUROLOGICAL AND NEURODEGENERATIVE DISEASES
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The present invention provides, in part, compounds of Formula (I): or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N- oxide, wherein: R1, R2, L, A, and E are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4- associated) disorders including, e.g., Alzheimer's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.
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Page/Page column 93
(2018/02/03)
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- DIHYDRO-PYRROLO-PYRIDINE DERIVATIVES
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The present invention provides, in part, compounds of Formula I, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N- oxide, wherein: (R1)a, (R2)b, (R3)c, L, A, and E are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4- associated) disorders including, e.g., Alzheimer's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.
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Page/Page column 86; 87
(2019/01/10)
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- FUMAGILLOL HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING SAME
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Disclosed herein, in part, are fumagillol compounds and methods of use in treating medical disorders, such as obesity. Pharmaceutical compositions and methods of making fumagillol compounds are provided. The compounds are contemplated to have activity against methionyl aminopeptidase 2.
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Paragraph 00277
(2017/03/08)
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- THIENOPYRIDINE CARBOXAMIDES AS UBIQUITIN-SPECIFIC PROTEASE INHIBITORS
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The disclosure relates to inhibitors of USP28 and/or USP25 useful in the treatment of cancers, inflammation, autoimmune diseases, and infectious diseases, having the Formula (I), where R1, R2, R3, R4, R5, R5', R6, R7, X, m, and n are described herein.
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Paragraph 00624
(2017/09/05)
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- Synthesis method of 7-hydroxymethyl-2,5-diazaspiro [3,4] octane-2-dimethylethylester
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The invention relates to a synthesis method of a compound of 7-hydroxymethyl-2,5-diazaspiro [3,4] octane-2-dimethylethylester, and mainly solves the technical problem that no industrial method suitable for industrial synthesis exists in the prior art. A compound 1 and triethyl-phosphite are used as raw materials for synthesizing and obtaining the final compound through eight steps. A reaction formula is shown in the specification.
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Paragraph 0008
(2017/12/27)
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- IMIDAZO[4,5-C]QUINOLINE DERIVATIVES AND USES THEREOF
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The present invention relates to substituted imidazo[4,5-c]quinoline derivatives represented by the compounds formula (I), processes for their preparation, pharmaceutical compositions comprising said compounds and their use in the treatment of diseases or disorders mediated by one or more kinases (such as PI3 kinase, mTOR and ALK-1), particularly proliferative diseases or disorders such as cancer. The compounds of formula (I) can also be used in the treatment of inflammation, angiogenesis related disorders and bacterial infections.
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Page/Page column 44
(2014/09/29)
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- Construction of multifunctional modules for drug discovery: Synthesis of novel thia/oxa-azaspiro[3.4]octanes
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New classes of thia/oxa-azaspiro[3.4]octanes are synthesized through the implementation of robust and step-economic routes. The targeted spirocycles have been designed to act as novel, multifunctional, and structurally diverse modules for drug discovery.
- Li, Dong Bo,Rogers-Evans, Mark,Carreira, Erick M.
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supporting information
p. 4766 - 4769
(2013/10/08)
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- 5,7-SUBSTITUTED-IMIDAZO[1,2-C]PYRIMIDINES
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Compounds of Formula I: and stereoisomers and pharmaceutically acceptable salts and solvates thereof in which R1, R2, R3, R4, R5, R6, X1 and X2 have the meanings given in the specification, are inhibitors of one or more JAK kinases and are useful in the treatment of autoimmune diseases, inflammatory diseases, rejection of transplanted organs, tissues and cells, as well as hematologic disorders and malignancies and their co-morbidities.
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Paragraph 00404
(2013/04/25)
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- PHENYL ALKANOIC ACID DERIVATIVES AS GPR AGONISTS
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The present invention relates to phenyl alkanoic acid derivatives (the compounds of Formula (I)); and their isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, polymorphs, N-oxides, S-oxides or carboxylic acid isosteres thereof. The invention also relates to processes for the preparation of compounds of Formula (I) and pharmaceutical compositions comprising one or more of the compounds of Formula (I). The said compounds and the pharmaceutical composition function as GPR (G-protein coupled receptor) agonists, particularly as GPR40 agonists, and are useful in the treatment of diseases or conditions mediated by GPR40. The present invention further relates to a method of treatment of diseases or conditions mediated by GPR40comprising administering to a subject in need thereof a therapeutically effective amount of the compounds of Formula (I).
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Page/Page column 137; 138
(2013/09/12)
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- The synthesis of 3-aryl-3-azetidinyl acetic acid esters by rhodium(I)-catalysed conjugate addition of organoboron reagents
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A practical route to 3-aryl-3-azetidinyl acetic acid esters is developed. The key step involves the rhodium(I)-catalysed conjugate addition of an organoboron reagent to an α,β-unsaturated alkene. Elaboration of one conjugate addition product to give a nov
- Collier, Philip N.
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scheme or table
p. 3909 - 3911
(2009/09/30)
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- [1H- PYRAZOLO [3, 4-B] PYRIDINE-4-YL] -PHENYLE OR -PYRIDIN-2-YLE DERIVATIVES AS PROTEIN KINASE C-THETA
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The present invention relates to compounds of formula (I) and (IA) useful as inhibitors of protein kinase (1a). The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions. (a) : in particular protein kinase C theta, wherein A and A' are independently -N- or -C(R+) -. Ring B is five- or six-membered saturated carbocyclic or heterocyclic R1, R2, R3, R4, R5, R6, R7, x and y are as described herein.
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Page/Page column 132
(2009/07/17)
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