205448-38-0

Upstream product

• 1160707-44-7 1-[4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl]ethan-1-one 
• 1449763-02-3 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)-3-(dimethylamino)propyl-2-en-1-one 
• 110-91-8 morpholine 
• 1394166-09-6 7-(3-chloropropyloxy)-6-methoxy-4(1H)-quinolinone 
• 205448-32-4 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline 
• 1394166-09-6 6-methyloxy-7-(4-(3-chloropropoxy))-4-4-hydroxyquinoline 
• 1394166-08-5 (Ε)-1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)-3-(dimethylamino)propyl-2-en-1-one 
• 1219937-97-9 1-[2-amino-5-methoxy-4-(3-morpholin-4-yl-propoxy)-phenyl]-ethanone 
• 109-94-4 formic acid ethyl ester 
• 1184831-17-1 1-[5-methoxy-4-(3-bromo-propoxy)-2-nitro-phenyl]-ethanone 
• 58113-30-7 4-(3-chloropropoxy)-3-methoxyacetophenone 
• 498-02-2 1-(3-methoxy-4-hydroxyphenyl)ethanone 
• 205448-37-9 5-((3-(3-morpholinopropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione 

Downstream Products

• 205448-32-4 4-chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline 
• 960299-44-9 4-(3-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine 
• 479690-10-3 3-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline 
• 849221-53-0 cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]-phenyl}-amide (4-fluoro-phenyl)-amide 
• 1449763-30-7 phenyl 3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenylcarbamate 
• 1449763-33-0 N¹-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)semicarbazide 
• 1428787-49-8 (E)-N⁴-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N¹-(benzylidene)semicarbazide 
• 1449763-21-6 (E)-N¹-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-N⁴-(4-fluorobenzylidene)semicarbazide 
• 1449763-22-7 (E)-N¹-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-N⁴-(4-chlorobenzylidene)semicarbazide 
• 1449763-23-8 (E)-N¹-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-N⁴-(4-trifluoromethoxybenzylidene)semicarbazide 
• 1449763-25-0 (E)-N¹-(3-fluoro-4-(6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yloxy)phenyl)-N⁴-(4-trifluoromethylbenzylidene)semicarbazide 
• 1428788-01-5 (E)-N⁴-phenyl-N¹-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzylidene)semicarbazide 

Relevant academic research and scientific papers

Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50= 1.21/2.15 nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure–activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 μM), A549 (IC50 = 0.39 μM), and MCF-7 (IC50 = 0.33 μM), which were 3.28–4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/c-Met kinase

The invention belongs to the technical field of chemical drug synthesis, and provides a compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/cMet kinase. The compound provided by the invention is prepared by amidation reaction of an intermediate A and an intermediate B. The compound provided by the invention has a strong effect of inhibiting Flt3/cMet kinase. The invention also discloses application of the compound and salt, solvate or prodrug thereof, or application of a pharmaceutical composition composed of one of the compound, salt, hydrate, solvate and prodrug thereof and an excipient in preparation of drugs for treating diseases caused by abnormal high expression of Flt3/cMet kinase, and application in drugs for treating and/or preventing proliferative diseases or cancers.

Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof

The invention provides a novel substituted pyrazolo [1, 5-a]pyrimidine compound and a preparation method and application thereof, and particularly relates to a pyrazolo [1, 5-a]pyrimidine-containing quinoline derivative shown as a general formula (I) and pharmaceutically acceptable salts thereof, and substituent groups X, Ar and A have meanings given in the specification. The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also relates to application of the compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and/or preventing cancers.

Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2

A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC50 values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC50 = 8.6 nM) and VEGFR2 (IC50 = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.

Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.

Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities

A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.

Design, synthesis and biological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone moiety as c-Met Inhibitors

Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, a series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against A549, HepG2, and MCF-7 cell lines. Eight of them are equal to more active than positive control Foretinib against one or more cell lines and enzyme. The most promising compound 53 showed superior activity to Foretinib, which possessed excellent c-Met kinase inhibition on a singledigital nanomolar level (IC50 = 0.6 nM), and cancer cells of A549 (IC50 = 0.003 μM), HepG2 (IC50 = 0.49 μM) and MCF-7 cells (IC50 = 0.006 μM). The result of AO single staining indicated that compound 53 could induce remarkable apoptosis of HepG2 cell.

Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5–2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α PDGFR-β c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.

Preparation and application of 6,7-disubstituted-4-aromatic quinoline compound

The invention relates to a 6,7-disubstituted-4-aromatic quinoline derivative shown as a general formula I as well as pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof, wherein substituents R1, X and Y have meanings given in the description. The invention further relates to a compound with a strong effect on inhibiting c-Met kinase shown as the general formula I and further relates to application of the compound and pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof to preparation of a drug for treating a disease caused by the abnormally-high expression of the c-Met kinase, in particular to application to preparation of a drug for treating and/or preventing a cancer.