223679-79-6

Upstream product

• 2033-24-1 cycl-isopropylidene malonate 
• 393-52-2 2-Fluorobenzoyl chloride 
• 445-29-4 o-fluoro-benzoic acid 

Downstream Products

• 873054-44-5 ivacaftor 
• 1394166-15-4 4-oxo-1-(2-(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carbonyl chloride 
• 1394165-15-1 N-(3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-1-(2-(trifluoromethyl)phenyl)-1,4-dihydrocinnoline-3-carboxamide 
• 1394166-18-7 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carbonyl chloride 
• 113846-18-7 ethyl 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 

Relevant academic research and scientific papers

PROCESSES FOR THE PREPARATION OF IVACAFTOR

The present invention provides processes for the preparation of ivacaftor using novel intermediates and a process for its preparation.

QUINOLINE AND CINNOLINE COMPOUNDS AND USE THEREOF

The present invention relates to a series of quinoline and cinnoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. And the compounds of general formula I show potent inhibitory activity gainst c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.

Quinoline and cinnoline derivatives and their applications

The present invention relates to a series of quinoline and cinnoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. And the compounds of general formula I show potent inhibitory activity gainst c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.

Synthesis and antitumor activity of novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-Oxo-1,4-dihydroquinoline-3-carboxamide moiety

A series of 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline-3-carboxamide moiety were designed, synthesized, and evaluated for their in vitro antitumor activity against the H460, HT-29, MKN-45, U87MG, and SMMC-7721 cancer cell lines. Most of the tested compounds showed potent activity and high selectivity toward the HT-29 and MKN-45 cell lines. Furthermore, compounds 21b, 21c, and 21i were further examined for their c-Met kinase activity and exhibited strong efficacy with IC50 values in the single-digit nanomolar range, which was comparable with the positive control foretinib. The most promising compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines, thus being 1.7-2.2 times more active than foretinib. Novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline- 3-carboxamide moiety were evaluated for their in vitro antitumor activity against several cancer cell lines. Compounds 21b, 21c, and 21i were also examined for their c-Met kinase activity in comparison to foretinib. Compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines and higher activity than foretinib.

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.

Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2,4- dialkylpyridine derivatives as selective A3 adenosine receptor antagonists

3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A3 adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186-3201). In the present study, ring- constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K(i) values at recombinant human and rat A3 adenosine receptors were determined using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)- 5'-N-methylcarbamoyladenosine). Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A(2A) receptors, and structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a β-fluoroethyl (7) or a γ- fluoropropyl ester (26) was favorable for human A3 receptor affinity, resulting in K(i) values of 4.2 and 9.7 nM, respectively, while the pentafluoropropyl analogue was clearly less potent at human A3 receptors. At the 2-, 3-, and 4-positions, fluoro or hydroxy substitution failed to enhance potency and selectivity at human A3 receptors. Several analogues were nearly equipotent at rat and human A3 receptors. To further define the pharmacophore conformationally, a lactam, a lactone, and thiolactones were tested in adenosine receptor binding. The most potent analogue in this group was compound 34, in which a thiolactone was formed between 3- and 4-positions and which had a K(i) value of 248 nM at human A3 receptors. Using affinity data and a general pharmacophore model for A3 adenosine receptor antagonists recently proposed, we applied comparative molecular field analysis (CoMFA) to obtain a three dimensional quantitative structure-activity relationship for pyridine derivatives, having good predictability (r2(pred) = 0.873) for compounds in the test set. A rhodopsin-based model of the human As receptor was built, and the pyridine reference ligand 2,3,4,5-tetraethyl-6-phenyl- pyridine-3-thiocarboxylate-5-carboxylate (MRS 1476) was docked in the putative ligand binding site. Interactions between receptor transmembrane domains and the steric and the electrostatic contour plots obtained from the CoMFA analysis were analyzed.