577691-56-6Relevant academic research and scientific papers
Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine
Molinaro, Carmela,Phillips, Eric M.,Xiang, Bangping,Milczek, Erika,Shevlin, Michael,Balsells, Jaume,Ceglia, Scott,Chen, Jiahui,Chen, Lu,Chen, Qinghao,Fei, Zhongbo,Hoerrner, Scott,Qi, Ji,De Lera Ruiz, Manuel,Tan, Lushi,Wan, Baoqiang,Yin, Jingjun
, p. 8006 - 8018 (2019)
A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.
Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation
Benson, Helen,Bones, Karen,Churchill, Gwydion,Ford, Gair,Frodsham, Lianne,Janbon, Sophie,Millington, Fiona,Powell, Lyn,Raw, Steven A.,Reid, Julie,Stark, Andrew,Steven, Alan
, p. 588 - 598 (2020/05/19)
Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.
PYRIDINE AND PYRAZINE COMPOUNDS AS INHIBITORS OF RIPK2
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Paragraph 0291; 0292, (2018/05/03)
The present invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein R1, R2, X, Y, and HET are as defined herein. The invention also relates to pharmaceutical compositions comprising these
FLUOROINDOLE DERIVATIVES AS MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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, (2017/03/28)
The present invention relates to compound of formula (I), or stereoisomers and pharmaceutically acceptable salts as muscarinic M1 receptor positive allosteric modulators. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to muscarinic M1 receptor.(Formula I) (I)
INHIBITORS OF RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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Page/Page column 48; 50, (2016/09/22)
Disclosed are compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
5- or 6-substituted benzofuran-2-carboxamide compounds and methods for using them
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, (2016/09/12)
The disclosure relates particularly to certain carboxamide, sulfonamide and amine compounds and pharmaceutical compositions thereof, and to methods of treating and ameliorating disorders and conditions related to the adiponectin pathway, sphingolipid metabolism, oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, among others. In certain embodiments, the compounds have the structures (I-1), (2-I) and (3-I) in which the variables are as described herein.
TBK/IKK INHIBITOR COMPOUNDS AND USES THEREOF
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Paragraph 0428; 0429, (2017/01/23)
The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as TBK/IKKε inhibitors.
Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
Nakajima, Yutaka,Inoue, Takayuki,Nakai, Kazuo,Mukoyoshi, Koichiro,Hamaguchi, Hisao,Hatanaka, Keiko,Sasaki, Hiroshi,Tanaka, Akira,Takahashi, Fumie,Kunikawa, Shigeki,Usuda, Hiroyuki,Moritomo, Ayako,Higashi, Yasuyuki,Inami, Masamichi,Shirakami, Shohei
, p. 4871 - 4883 (2015/08/03)
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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, (2015/02/25)
The present invention relates to compounds of formula I: in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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, (2015/02/25)
The present invention relates to compounds of formula I in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
