907572-28-5

Upstream product

• 211108-52-0 (±)-cis-4-benzylamino-3-fluoropiperidine-1-carboxylic acid tert-butyl ester 
• 211108-50-8 tert-butyl-3-fluoro-4-oxopiperidine-1-carboxylate 
• 100-46-9 benzylamine 
• 79099-07-3 N-tert-butyloxycarbonylpiperidin-4-one 
• 211108-48-4 tert-butyl 4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate 
• 211108-52-0 cis-4-benzylamino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester 

Downstream Products

• 907544-17-6 tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate 
• 1356963-16-0 (3R,4S)-N-benzyl-3-fluoropiperidin-4-amine HCl salt 
• 1356963-17-1 (3R,4S)-N-benzyl-3-fluoro-1-(3-methoxy-4-nitrophenyl)piperidin-4-amine 

Relevant academic research and scientific papers

Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation

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

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

Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3

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.

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099)

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy

The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochemical activity an

CHEMICAL COMPOUNDS

Compounds of formula (I) and their pharmaceutically acceptable salts are described: formula (I). Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.