- Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors
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Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure-activity relationship enabled efficient potency optimization.
- Schade, Markus,Merla, Beatrix,Lesch, Bernhard,Wagener, Markus,Timmermanns, Simone,Pletinckx, Katrien,Hertrampf, Torsten
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supporting information
p. 11801 - 11808
(2020/11/26)
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- Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications
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C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.
- Kawamata, Yu,Vantourout, Julien C.,Hickey, David P.,Bai, Peng,Chen, Longrui,Hou, Qinglong,Qiao, Wenhua,Barman, Koushik,Edwards, Martin A.,Garrido-Castro, Alberto F.,Degruyter, Justine N.,Nakamura, Hugh,Knouse, Kyle,Qin, Chuanguang,Clay, Khalyd J.,Bao, Denghui,Li, Chao,Starr, Jeremy T.,Garcia-Irizarry, Carmen,Sach, Neal,White, Henry S.,Neurock, Matthew,Minteer, Shelley D.,Baran, Phil S.
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supporting information
p. 6392 - 6402
(2019/04/17)
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- POLY-ADP RIBOSE POLYMERASE (PARP) INHIBITORS
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The present invention is related to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: The present invention is also related a method of treating a subject with a disease which can be ameliorated by inhibition of poly(ADP-ribose)polymerase (PARP). The definitions of the variables are provided herein.
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Page/Page column 87
(2018/07/29)
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- Site-Selective Copper-Catalyzed Amination and Azidation of Arenes and Heteroarenes via Deprotonative Zincation
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Arene amination is achieved by site-selective C-H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amidodiethylzincate base that is effective for a wide range of arenes, including nonactivated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine, and isoquinoline. An analogous C-H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable and diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogues of natural product (-)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.
- Hendrick, Charles E.,Bitting, Katie J.,Cho, Seoyoung,Wang, Qiu
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supporting information
p. 11622 - 11628
(2017/08/30)
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- A tuned bicyclic proazaphosphatrane for catalytically enhanced n-arylation reactions with aryl chlorides
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The N-arylation of various amines with aryl chlorides proceeded in good-to-excellent yields in the presence of P[N{(p-NMe2)C6H4CH2}CH2CH2]3N (1e, a new electron-rich proazaphosphatrane ligand) and small amounts of Pd2(dba)3 (dba = dibenzylideneacetone). This catalytic system was also very effective for the synthesis of carbazoles. An efficient palladium-catalyzed N-arylation reaction of amines under mild conditions with a tuned bicyclic proazaphosphatrane has been developed.
- Kim, So Han,Kim, Min,Verkade, John G.,Kim, Youngjo
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p. 1954 - 1960
(2015/03/18)
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- "Throwing away" a different ancillary ligand to enhance the catalytic activity at room temperature
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A considerable effort in ligand design for catalysis in recent years has led to remarkable achievements in cross-coupling reactions. In this work, we show that a careful selection of the ancillary ligands that complete the catalyst/precatalyst can provide an extra level of performance. Low loadings of [(IPr)PdCl2(TEA)] {IPr = 1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazole-2-ylidene, TEA = triethylamine} catalyze the Buchwald-Hartwig amination reactions of aryl chlorides at room temperature in excellent yields, without the need for an inert atmosphere to set up or perform the reactions.
- Guest, Daniel,Chen, Ming-Tsz,Tizzard, Graham J.,Coles, Simon J.,Turner, Michael Lewis,Navarro, Oscar
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supporting information
p. 2200 - 2203
(2015/04/27)
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- "throwing away" a different ancillary ligand to enhance the catalytic activity at room temperature
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A considerable effort in ligand design for catalysis in recent years has led to remarkable achievements in cross-coupling reactions. In this work, we show that a careful selection of the ancillary ligands that complete the catalyst/precatalyst can provide
- Guest, Daniel,Chen, Ming-Tsz,Tizzard, Graham J.,Coles, Simon J.,Turner, Michael Lewis,Navarro, Oscar
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p. 2200 - 2203
(2014/05/20)
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- Solvent free N-Boc protection of amines using amberlystr a 21 solid base resin as a reusable heterogeneous catalyst
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An efficient, environmentally benign, highly facile and convenient synthetic protocol for the selective t-butyl carboxylation of aliphatic, aromatic and heterocyclic amines using AmberlystR A 21 catalyst; a mild basic solid resin under solvent free conditions is reported. This method explores several advantages such as reusability of the heterogeneous catalyst, cleaner reaction profile, mild and solvent free system, short reaction time, operational simplicity, high conversions , excellent product yields and low cost of the catalyst. Furthermore since the catalyst is mild basic, decomposition of the carbamate formed is not observed if the reaction is continued for prolonged time as in the case of Lewis acid catalyzed N-Boc protection. This makes the present protocol a useful and attractive for N-Boc protection of amines.
- Tekale, Sunil U.,Kauthale, Sushama S.,Pawar, Rajendra P.
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p. 1619 - 1623
(2013/09/12)
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- THERAPEUTICALLY ACTIVE COMPOUNDS FOR USE IN THE TREATMENT OF CANCER CHARACTERIZED AS HAVING AN IDH MUTATION
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Compounds and compositions comprising compounds useful in the treatment of cancer are described herein. The compounds and compositions can be used to modulate an isocitrate dehydrogenase (IDH) mutant (e.g., IDHIm or IDH2m) having alpha hydroxyl neoactivity
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Page/Page column 100
(2011/06/26)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 50-51
(2011/04/14)
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- (t-Bu)2PN=P(i-BuNCH2CH2)3N: New efficient ligand for palladium-catalyzed C-N couplings of aryl and heteroaryl bromides and chlorides and for vinyl bromides at room temperature
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(Chemical Equation Presented) By employing Pd(OAc)2, Cs 2CO3, or NaOH, and the new ligand (t-Bu) 2PN=P(i-BuNCH2CH2)3N (3a), an electronically diverse array of aryl bromides and chlorides possessing base-sensitive substituents (nitro, ester, and keto) provide coupling products with bulky aryl amines in good to excellent yields. Aryl halides possessing other functional groups including cyano, amino, trifluoromethyl, and phenol, coupled with equal ease, producing highly functionalized amines in good to excellent yields. Moreover, an aryl chloro group can be preserved in the presence of a bromo substituent under our reaction conditions. BOC-protected amines also participated efficiently. Heterocyclic bromides and chlorides underwent clean couplings with amines in excellent yields. An important strength of our protocol is the use of lower palladium loadings than those reported earlier, without compromising yields. The air-stable palladium complex (η3-cinnamyl)PdCl·(3a) (5) was also employed successfully in C-N coupling reactions while the crotyl analogue was less efficacious. The 3a/Pd(OAc)2 catalyst system promotes, for the first time, efficient coupling of vinyl bromides with a variety of amines to produce imines and enamines at room temperature.
- Reddy, Ch. Venkat,Kingston, Jesudoss V.,Verkade, John G.
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p. 3047 - 3062
(2008/09/19)
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- ACETYLENE DERIVATIVES AS STEAROYL COA DESATURASE INHIBITORS
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The present invention provides Stearoyl CoA Desaturase (SCD) inhibitors, hi particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by Stearoyl CoA Desaturase 1 (SCD 1) inhibitors. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by Stearoyl CoA Desaturase (SCD) inhibitors.
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Page/Page column 50
(2008/12/05)
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- Molecular iodine-catalyzed facile procedure for N-Boc protection of amines
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An efficient and practical protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)2O in the presence of a catalytic amount of molecular iodine (10 mol%) under solvent-free conditions at ambient temperature is presented.
- Varala, Ravi,Nuvula, Sreelatha,Adapa, Srinivas R.
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p. 8283 - 8286
(2007/10/03)
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- Efficient palladium catalysts for the amination of aryl chlorides: A comparative study on the use of phosphium salts as precursors to bulky, electron-rich phosphines
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Alkyl-di-(1-adamantyl)phosphonium salts are practical ligand precursors for the palladium-catalyzed amination of aryl chlorides. In the presence of typically 0.5 mol% Pd(OAc)2 and 1 mol% of ligand precursor a variety of activated and deactivated aryl chlorides can be aminated in good to excellent yield (73-99%). Applying optimized conditions catalyst turnover numbers up to 10,000 have been achieved.
- Tewari, Amit,Hein, Martin,Zapf, Alexander,Beller, Matthias
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p. 9705 - 9709
(2007/10/03)
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- Scope and limitations of Pd2(dba)3/P(i-BuNCH 2CH2)3N-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides
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Proazaphosphatrane ligands in combination with Pd2(dba) 3 generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides. In particular, commercially available P(i-BuNCH 2-CH2)3N is a highly general and efficient ligand, allowing the coupling of an electronically diverse set of aryl chlorides, including chloropyridines, with a wide variety of amines using 1 mol % of Pd at 100 °C. Either a 1:1 or 2:1 ratio of ligand to Pd was found to be effective. This catalyst system performs exceptionally well for sterically hindered substrates, even with only 0.25 mol % of Pd. It is shown that NaOH can also be used as the base (instead of NaO-t-Bu) allowing functionalized substrates to participate in these reactions.
- Urgaonkar, Sameer,Verkade, John G.
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p. 9135 - 9142
(2007/10/03)
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