118994-89-1Relevant articles and documents
A general route to the Streptomyces-derived inthomycin family: The first synthesis of (+)-inthomycin B
Webb, Michael R.,Donald, Craig,Taylor, Richard J. K.
, p. 549 - 552 (2006)
A concise, convergent and stereocontrolled synthesis of (+)-inthomycin B, based on the Stille coupling of a stannyl-diene with an oxazole vinyl iodide unit, is described. The asymmetric centre was introduced using the Kiyooka ketene acetal/amino acid-derived oxazaborolidinone procedure.
Structure-based lead optimization to improve antiviral potency and ADMET properties of phenyl-1H-pyrrole-carboxamide entry inhibitors targeted to HIV-1 gp120
Curreli, Francesca,Belov, Dmitry S.,Kwon, Young Do,Ramesh, Ranjith,Furimsky, Anna M.,O'Loughlin, Kathleen,Byrge, Patricia C.,Iyer, Lalitha V.,Mirsalis, Jon C.,Kurkin, Alexander V.,Altieri, Andrea,Debnath, Asim K.
, p. 367 - 391 (2018)
We are continuing our concerted effort to optimize our first lead entry antagonist, NBD-11021, which targets the Phe43 cavity of the HIV-1 envelope glycoprotein gp120, to improve antiviral potency and ADMET properties. In this report, we present a structure-based approach that helped us to generate working hypotheses to modify further a recently reported advanced lead entry antagonist, NBD-14107, which showed significant improvement in antiviral potency when tested in a single-cycle assay against a large panel of Env-pseudotyped viruses. We report here the synthesis of twenty-nine new compounds and evaluation of their antiviral activity in a single-cycle and multi-cycle assay to derive a comprehensive structure-activity relationship (SAR). We have selected three inhibitors with the high selectivity index for testing against a large panel of 55 Env-pseudotyped viruses representing a diverse set of clinical isolates of different subtypes. The antiviral activity of one of these potent inhibitors, 55 (NBD-14189), against some clinical isolates was as low as 63 nM. We determined the sensitivity of CD4-binding site mutated-pseudoviruses to these inhibitors to confirm that they target HIV-1 gp120. Furthermore, we assessed their ADMET properties and compared them to the clinical candidate attachment inhibitor, BMS-626529. The ADMET data indicate that some of these new inhibitors have comparable ADMET properties to BMS-626529 and can be optimized further to potential clinical candidates.
Compounds and methods of use
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Page/Page column 517-519, (2021/08/04)
Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X1, X2, X3, X4, Y, A, L1, L2, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.
Application of C-H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib
Bream, Robert N.,Clark, Hugh,Edney, Dean,Harsanyi, Antal,Hayler, John,Ironmonger, Alan,Mc Cleary, Nadine,Phillips, Natalie,Priestley, Catherine,Roberts, Alastair,Rushworth, Philip,Szeto, Peter,Webb, Michael R.,Wheelhouse, Katherine
supporting information, p. 529 - 540 (2021/03/01)
This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C-H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.
Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach
Edney, Dean,Hulcoop, David G.,Leahy, John H.,Vernon, Lois E.,Wipperman, Mark D.,Bream, Robert N.,Webb, Michael R.
, p. 368 - 376 (2018/03/22)
This paper describes the discovery and development of a flexible route to two candidate drug molecules by a common intermediate approach. Key reactions include Negishi and Suzuki couplings to form biaryl bonds. Conditions for a Miyaura borylation of heteroaryl bromides were also developed. Heteroaryl trifluoroborates and aryl chlorides were used as coupling partners in the Suzuki reaction, thereby minimizing detrimental side reactions such as protodeboronation and oxidative homocoupling. A complementary set of reaction conditions using pinacolboronates with potassium bifluoride as an additive were also developed and used to make 5 kg of drug substance for use in early-phase clinical trials.
Indazole derivatives for use in the treatment of influenza virus infection
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Page/Page column 165, (2016/06/01)
The present invention is directed to compounds for use in the treatment or prevention of influenza virus infection.
Polymorphs and Salts
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Paragraph 0324; 0325; 0326, (2013/08/15)
The present invention is directed to a polymorph of a compound and salts of a compound and polymorphs thereof, which compound is an inhibitor of kinase activity.
POLYMORPHS AND SALTS OF N- [5- [4- (5- { [(2R,6S) -2, 6 - DIMETHYL - 4 -MORPHOLINYL] METHYL} - 1, 3 - OXAZOL - 2 - YL) - 1H- INDA ZOL-6-YL] -2- (METHYLOXY) - 3 - PYRIDINYL] METHANESULFONAMIDE
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Page/Page column 60, (2012/03/27)
The present invention is directed to novel polymorphs and salts of a compound which is an inhibitor of kinase activity.
POLYMORPHS AND SALTS OF 6-(1H-INDOL-4-YL)-4-(5- { [4-(1-METHYLETHYL)-1-PI PERAZINYL] METHYL} -1,3-OXAZOL-2-YL)-1H-INDAZOLE AS PI3K INHIBITORS FOR USE IN THE TREATMENT OF E.G. RESPIRATORY DISORDERS
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Page/Page column 55-56, (2012/05/19)
The present invention is directed to a polymorph of a compound of formula (II) and salts and polymorphs thereof, which is an inhibitor of PI3 kinase activity.
Highly enantioselective mukaiyama aldol reactions catalyzed by a chiral oxazaborolidinium ion: Total synthesis of (-)-inthomycin C
Senapati, Bidyut Kumar,Gao, Lizhu,Lee, Sung Il,Hwang, Geum-Sook,Ryu, Do Hyun
supporting information; experimental part, p. 5088 - 5091 (2011/01/05)
A cationic oxazaborolidinium-catalyzed asymmetric Mukaiyama aldol reaction of (1-methoxy-2-methyl-propenyloxy)-trimethylsilane with various aldehydes including α,β-disubstituted acroleins has been developed in high yields and enantioselectivities. The synthetic utility of this methodology was demonstrated in the first short synthesis of naturally occurring inthomycin C in high enantiopurity.
