1422385-97-4

Upstream product

• 98548-90-4 methyl pyrrolidine-3-carboxylate 
• 625-99-0 3-iodochlorobenzene 
• 6393-19-7 3-chloro-N-hydroxyethyl aniline 
• 108-42-9 3-chloro-aniline 
• 133747-67-8 methyl 1-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate 
• 97-65-4 2-methylenesuccinic acid 
• 92847-41-1 1-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid 

Downstream Products

• 1086374-92-6 1‐(3‐chlorophenyl)pyrrolidine‐3‐carboxylic acid 

Relevant academic research and scientific papers

Palladium-catalyzed intramolecular carbene insertion into C(sp3)-H bonds

A palladium-catalyzed carbene insertion into C(sp3)-H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd0 and PdII, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium-catalyzed C(sp3)-C(sp3) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp3)-H bond functionalization reaction involves an unprecedented concerted metalation-deprotonation step. Pd in action: Palladium has been used to catalyze the C(sp3)-H insertion of metal carbenoids derived from α-diazoesters to form pyrrolidines through intramolecular assembly of C(sp3)-C(sp3) bonds. A reaction mechanism involving a metalation-deprotonation step instead of the usual concerted but asynchronous process is proposed.

Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.

Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups

Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.

Transition Metal-Catalysed Intramolecular Carbenoid C?H Insertion for Pyrrolidine Formation by Decomposition of α-Diazoesters

The use of Pd-, Rh(II)- and Ru(II)-based catalysts has been explored in the transition metal-catalysed intramolecular carbenoid C?H insertion of α-diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate-dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)-catalysts were as efficient as [Rh(Ph3CCO2)2]2 in promoting the C(sp3)?H insertion of ortho-substituted anilines. In contrast, for anilines bearing meta- and para-substituents, the Rh(II)-catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p-cymene)Cl2]2 was the most efficient catalyst for the insertion reaction of the N-benzyl-N-phenyl and N,N-dibenzyl α-diazoesters, while the C(sp3)?H insertion of the N-benzylsulfonamide substrate was only promoted by [Rh(Ph3CCO2)2]2. According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)- and Ru(II)-catalysed C(sp3)?H insertions differs considerably from that typically proposed for the Rh(II)-catalysed transformation. Whereas the Pd(0)-catalysed reaction involves a Pd-mediated 1,5-H migration from the C(sp3)?H bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)-promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)-catalysed transformation. (Figure presented.).

TETRAHYDROISOQUINOLINES CONTAINING SUBSTITUTED AZOLES AS FACTOR XIA INHIBITORS

The present invention provides compounds of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

NOVEL MACROCYCLES AS FACTOR XIA INHIBITORS

The present invention provides compounds of Formula (Ia): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.