cas 162012-70-6, 4-Chloro-7-fluoro-6-nitro-quinazoline

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Potential applications of clickable probes in EGFR activity visualization and prediction of EGFR-TKI therapy response for NSCLC patients
The epithelial growth factor receptor (EGFR) is abnormally overexpressed on the cell surface of cancer cells and is strongly associated with cancer cell proliferation, migration, differentiation, apoptosis, and angiogenesis. Tools enabling the visualization of EGFR in a structure-function approach are highly desirable to predict EGFR mutations and guide EGFR tyrosine kinase inhibitor (TKI) treatment making. Here, we describe the design, synthesis, and application of new, potent and selective clickable probes 13 (HX03), 20 (HX04) and 24 (HX05) by introducing an alkyne ligation handle to visualize EGFR activity in living cancer cells and tissue slices. These clickable probes are versatile chemical tools based on the key pharmacophore (4-anilinoquinazoline) of EGFR-TKIs (e.g., canertinib, dacomitinib and afatinib) and are able to irreversibly target the kinase domain of EGFR. Among them, 13 exhibits the highest reactivity towards EGFR kinase, particularly to EGFR kinase with primary mutations. Using activity-based protein profiling strategy, 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. Moreover, 13 was applied to visualize EGFR mutant activity in tumour tissues from non-small-cell lung cancer (NSCLC) xenograft mouse models, and patients with NSCLC for the prediction of EGFR-TKI sensitivity. These results demonstrate that strategically designed EGFR-TKI-based probes allow discriminating EGFR mutations in human tissues and hold promise as useful diagnostic tools in predicting EGFR-TKI therapy response.
Bi, Liyun,Deng, Hui,Lei, Qian,Li, Weimin,Li, Ying,Shang, Weidong,Yang, Na,Yu, Zhiyi
(2022/01/13)

EFGR INHIBITOR, PREPARATION METHOD THEREFOR, AND APPLICATION THEREOF
An EGFR inhibitor having the structure of formula (I), a preparation method therefor, a pharmaceutical composition containing same, a use of same as an EGFR inhibitor, and a use of same in preparing a drug for treating and/or preventing a cancer, a tumor, or a metastatic disease at least partially related to an EGFR exon 20 insertion, deletion, or other mutation, and in particular a use in preparing a drug for treating and/or preventing a hyperproliferative disease and an induced cell death disorder. Each substituent of formula (I) has the same definition as in the description.
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Page/Page column 34-35

(2022/02/24)

ALKYNYL QUINAZOLINE COMPOUNDS
The present disclosure relates to compounds of Formula (I'): and pharmaceutically acceptable salts and stereoisomers thereof. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans.
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Paragraph 0742; 0914; 0938; 0965; 0971; 0988; 0991; 1039

(2021/02/19)

Preparation method of high-purity quinazoline drug intermediate
The invention discloses a preparation method of a high-purity quinazoline drug intermediate N-(3-acetylene phenyl)-7-fluorine-6-nitro-4-aminoquinazoline, which comprises the following steps: by taking 4-hydroxy-7-fluorine-6-nitroquinazoline as a raw mater
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Paragraph 0006; 0013-0016

(2021/07/17)

Tyrosine kinase inhibitor and pharmaceutical application thereof
The invention relates to a tyrosine kinase inhibitor containing a quinazoline derivative in the fields of tumor treatment medicines and the like, and application of the tyrosine kinase inhibitor in treatment medicines for inhibiting and treating diseases caused by overexpression of tyrosine kinase. The active ingredient of the tyrosine kinase inhibitor is a quinazoline derivative with a structure shown in the following formula: a functional group containing XCH2 (CH2) nC = O is introduced on the basis of a quinazoline structure, and the functional group is easily combined with cysteine sulfydryl through nucleophilic reaction to form a covalent bond so that the activity of tyrosine kinase is irreversibly inhibited.
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Paragraph 0019; 0021-0023

(2021/08/19)

POLYMORPHIC FORMS AND RELATED USES
The present disclosure relates to polymorphic forms of the receptor tyrosine kinases inhibitor compound of formula (I), pharmaceutical compositions comprising the polymorphic forms, methods of making the polymorphic forms, and methods of using the polymor
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Page/Page column 73

(2021/10/02)

Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
(2021/01/25)

TYROSINE KINASE INHIBITOR COMPOSITIONS, METHODS OF MAKING AND METHODS OF USE
The present disclosure relates to new compounds of formula I and pharmaceutically acceptable salts and stereoisomers thereof, as inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of abnormal cell growth in mammals, (e.g., humans).
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Page/Page column 218; 219; 226

(2020/05/13)

In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models
Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts.
Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Shi, Jingli,Hong, Jian
(2020/04/15)

QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITOR, COMPOSITIONS, METHODS OF MAKING THEM AND THEIR USE
The present disclosure relates to new compounds or pharmaceutically acceptable salts or stereoisomers thereof of formula I as inhibitors of receptor tyrosine kinases (RTK), in particular extracellular mutants of ErbB-receptors. The present disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the treatment of cancer in mammals (e.g. humans).
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Page/Page column 393-394; 477; 503

(2020/05/13)

Design, synthesis and antitumor activity of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline
Background: Cancer continues to pose a great problem and burden on society despite new treatment options. While surgery, radiotherapy, and chemotherapy have led to major improvements in patient prognosis, newer treatments are needed to more effectively manage this disease in its advanced stage. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. The family of EGFR has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma. Thus, it is a good strategy that design anticancer agents by inhibiting the EGFR pathway. Methods: We group to obtain the six series compounds (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d). Hence we disclosed the design, synthesis and antitumor activity of novel quinazoline analogues against EGFR overexpression cancer cells A549 (human lung cancer), HepG-2 (human liver cancer), MCF-7 (human breast cancer) and PC-3 (human prostate cancer) and as well as the inhibitory on EGFR kinase. Moreover, apoptosis by acridine orange single staining and docking studies were presented in this paper as well. Results: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the half maximal inhibitory concentration (IC50) values against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty target compounds showed moderate to excellent (1.49 - 50 μM) cytotoxicity activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.49 ± 0.17 μM, 2.90 ± 0.24 μM, 1.85 ± 0.19 μM, 3.30 ± 0.22 μM, respectively. What’s more, the secondary amines were introduced to the target compounds to improve the water-soluble. The results showed that the compounds were beneficial to the cytotoxicity activity. Furthermore, the results prompted us that this series of compounds may be a kind of potential epidermal growth factor receptor (EGFR) kinase inhibitors. Conclusion: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4tetrahydroquinoline moiety (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the IC50 values of cytotoxicity against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty synthesized compounds showed moderate to excellent cytotoxicity activity against the different cancer cells. Especially, the compound 13a exerted antitumor effects in a dosage-dependent manner and the IC50 values of compound 13a were 1.49 μM, 2.90 μM, 1.85 μM and 3.30 μM against A549, HepG-2, MCF-7 and PC-3, respectively. From the antitumor activity data show that the compounds possessed selectivity for A549 and MCF-7 cancer cell lines. It meant that the compounds had better treatment effect on lung cancer and breast cancer. On the whole, the compounds substituted by 1,2,3,4-tetrahydroquinoline at C-4 position of quinazoline and (S)-tetrahydrofuran-3-ol at C-8 position of quinazoline were beneficial to the cytotoxicity activity. From the result of acridine orange (AO) single staining which indicated the compound 13a could induce apoptosis of A549 cells. From the result of Docking Studies, we hypothesized that the C-4 position of quinazoline were substituted by 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline with the equal influence of the cytotoxicity activity. Overall, the results prompted us that this series of compounds may be a kind of potential EGFR kinase inhibitors.
Ou Yang, Yiqiang,Zhao, Bingbing,Chen, Xiuying,Wang, Caolin,Zhang, Hong,Jia, Shuang,Zhu, Wufu,Zheng, Pengwu
p. 533 - 546
(2019/06/20)

Novel protein inhibitor and preparation method and application thereof
The invention provides a novel protein inhibitor and a preparation method and application thereof, and specifically provides a compound as shown in a formula I, wherein definitions of all groups are described in the specification. The compound has good Bcl-2 family protein inhibition activity and can be used for preparing a series of medicines for treating diseases related to Bcl-2 family proteinactivity.
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(2019/11/12)

Discovery of new quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors and their anticancer activities – Part 1
Overexpression of EGFR and HER2 are observed in many breast, ovarian, colon and prostate cancers. The second and third generation irreversible EGFR/HER2 dual kinase inhibitors became popular after the approval of Afatinib by FDA to overcome the mutation related problem. To find efficacious drug candidates, a series of novel quinazoline derivatives were designed, synthesized and evaluated as dual EGFR/HER2 tyrosine kinase (TK) inhibitors. Selected twenty four compounds were reported here with significant inhibitory activities against EGFR/HER2 tyrosine kinases. Several compounds showed nanomolar IC50 values. In vitro studies of quinazoline derivatives were done on NCI-H1975, HCC827, A431, MDA MB-453 cell lines. The compounds 1a, 1d and 1v were found more potent compared to standard drug afatinib. In vivo efficacy study of 1d on nude mice NCI-H1975 tumour xenograft model was discussed.
Das, Debasis,Xie, Lingzhi,Wang, Jingbing,Xu, Xin,Zhang, Zonghua,Shi, Jingli,Le, Xiaoyong,Hong, Jian
p. 591 - 596
(2019/01/04)

STEFs: Activated Vinylogous Protein-Reactive Electrophiles
Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.
Hansen, Bente K.,Loveridge, Christopher J.,Thyssen, Stine,W?rmer, Gustav J.,Nielsen, Andreas D.,Palmfeldt, Johan,Johannsen, Mogens,Poulsen, Thomas B.
p. 3533 - 3537
(2019/02/14)

Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline as potential EGFR inhibitors
Eight series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Most of the forty nine target compounds showed excellent antiproliferative activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.09 ± 0.04 μM, 1.34 ± 0.13 μM and 1.23 ± 0.09 μM, respectively. Eight selected compounds were further selected to evaluated for the inhibitory activity against EGFR kinase. Three of them showed equal activity against EGFR kinase to positive control afatinib. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that the compound 13a could induce apoptosis of human lung cancer A549 cells.
OuYang, Yiqiang,Zou, Wensheng,Peng, Liang,Yang, Zunhua,Tang, Qidong,Chen, Mengzi,Jia, Shuang,Zhang, Hong,Lan, Zhou,Zheng, Pengwu,Zhu, Wufu
p. 29 - 43
(2018/05/24)

Design, synthesis, antiproliferative activity and docking studies of quinazoline derivatives bearing oxazole or imidazole as potential EGFR inhibitors
Six series of quinazoline derivatives bearing oxazole or imidazole (8a-f, 9a-f, 10a-d, 11a-f, 12a-d and 13a-i) were designed, synthesized and their IC50 values evaluated against three cancer cell lines (A549, MCF-7 and PC-3). Most of the thirty-five target compounds showed excellent antiproliferative activity against one or several cancer cell lines. Compound 12a showed the best activity against A549, MCF-7 and PC-3 cancer cell lines, with IC50 values of 1.90 ± 0.13 μM, 2.23 ± 0.28 μM and 2.03 ± 0.14 μM, respectively. Four selected compounds (8a, 9d, 10a and 12a) were further evaluated for the inhibitory activity against EGFR kinase. AnnexinV-FITC, propidium iodide (PI) double staining and acridine orange single staining results indicated that compound 12a could induce apoptosis of human lung cancer A549 cells.
OuYang, Yiqiang,Wang, Caolin,Zhao, Bingbing,Xiong, Hehua,Xiao, Zhen,Zhang, Bingliang,Zheng, Pengwu,Hu, Jiayi,Gao, Yanli,Zhang, Manli,Zhu, Wufu,Xu, Shan
p. 17203 - 17215
(2018/11/01)

Quinazoline compound containing oxazole or imidazole structure and application thereof
The invention discloses a quinazoline compound containing an oxazole or imidazole structure, as well as geometrical isomers and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. The quinazoline compound containing the oxazole or imidazole structure as well as the pharmaceutically acceptable salts, hydrates and solvates thereof serving as active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare compositions and prepared into clinically acceptable dosage forms. The invention further discloses application of the compounds in preparation of medicines for treating and/or preventing hyperplastic diseases, application in preparation of medicines for treating and/or preventing cancers, and application in preparation of medicines for treating and/or prostatic cancer, lung cancer and cervical cancer.
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(2018/09/14)

Having inhibitory anti-apoptosis protein active compound and its preparation and use (by machine translation)
The present invention has offered a kind of inhibiting anti-apoptosis protein active compound and its preparation and use. In particular, the invention provides a compound of formula I the following; wherein the definition of each group as described in the specification. The compounds of the invention has very good Bcl - 2 family protein inhibitory activity, can be used for preparing a series of treating Bcl - 2 family protein activity associated with the disease. (by machine translation)
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(2018/10/19)

Method for synthesizing quinazoline antitumor drug intermediate
The invention discloses a method for synthesizing a quinazoline antitumor drug intermediate, wherein the intermediate is a 4-chloroquinazoline compound; and the method comprises the following steps: sealing and reacting 6,7-disubstituted quinazolinone of formula (II) with a chlorinating reagent at 70-80 DEG C for 4-5 hours in an inert gas protection atmosphere in the case of using macroporous resin and triethylenediamine as catalysts in an organic solvent; and after reaction, naturally cooling, concentrating in vacuum, recrystallizing and purifying to obtain the 4-chloroquinazoline compound offormula (I), wherein R1 and R2 are independently selected from methoxyl, nitro, amino, 2-methoxyethoxy, halogen and acetoxy. The method provided by the invention has advantages of mild reaction conditions, short reaction time, low cost, high purity, economy and environmental protection, easy preparation of intermediates of pharmaceutical raw materials, remarkable industrial advantages, and broadmarket prospect and application potential.
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Paragraph 0045-0046; 0048; 0050; 0051-0052

(2018/08/03)

SALTS OF QUINAZOLINE DERIVATIVE AND METHOD FOR PREPARING SAME
The present application relates to maleates of a compound of Formula I, methods for preparing the same, pharmaceutical compositions thereof and uses thereof in the treatment of tumors, such as non-small cell lung cancer, breast cancer, and other malignant
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Paragraph 0035; 0036

(2018/03/02)

Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors
A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
Hou, Weijie,Ren, Yan,Zhang, Zhenhua,Sun, Huan,Ma, Yongfen,Yan, Bo
p. 1740 - 1750
(2018/03/12)

PROCESS FOR THE PREPARATION OF N-[4-[(3-CHLORO-4-FLUORO PHENYL) AMINO]-7-[[(3s-TETRAHYDRO-3-FURANYL]OXY]-6-QUINAZOLINYL]-4-(DIMETHYL AMINO)-(2E)-2-BUTENAMIDE (2Z)-2-BUTENEDIOATE (1 :2) AND ITS POLYMORPHS THEREOF
The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:
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Paragraph 0210

(2018/11/21)

Design, synthesis, and docking studies of quinazoline analogues bearing aryl semicarbazone scaffolds as potent EGFR inhibitors
Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a–o and 10a–o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 9o showed the best activity against A549, HepG2, MCF-7 and PC-3 cancer cell lines and EGFR kinase, with the IC50 values of 1.32?±?0.38?μM, 0.07?±?0.01?μM, 0.91?±?0.29?μM and 4.89?±?0.69?μM, which were equal to more active than afatinib (1.40?±?0.83?μM, 1.33?±?1.28?μM, 2.63?±?1.06?μM and 3.96?±?0.59?μM), respectively. Activity of the most promising compound 9o (IC50 56?nM) against EGFR kinase was slightly lower to the positive compound afatinib (IC50 1.6?nM) but more active than reference staurosporine (IC50 238?nM). The result of flow cytometry, with the dose of compound 9o increasing, which indicated the compound 9o could induce remarkable apoptosis of A549 and cells in a dose dependent manner. Structure–activity relationships (SARs) and docking studies indicated that replacement of the cinnamamide group by aryl semicarbazone scaffolds slightly decreased the anti-tumor activity. The results suggested that hydroxy substitution at C-4 had a significant impact on the activity and replacement of the tetrahydrofuran group by methyl moiety was not beneficial for the activity.
Tu, Yuanbiao,Wang, Caolin,Xu, Shan,Lan, Zhou,Li, Wei,Han, Jiaqian,Zhou, Yuanzhang,Zheng, Pengwu,Zhu, Wufu
p. 3148 - 3157
(2017/05/29)

Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor-Based Spin Labeling
The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof-of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available.
Yin, Dongsheng M.,Hannam, Jeffrey S.,Schmitz, Anton,Schiemann, Olav,Hagelueken, Gregor,Famulok, Michael
p. 8417 - 8421
(2017/07/11)

Quinazoline compound containing acylhydrazone structure and application thereof
The invention discloses a quinazoline compound containing an acylhydrazone structure. The quinazoline compound is as shown in a formula I in the description. The invention relates to the quinazoline compound comprising the acylhydrazone structure, a pharmaceutically acceptable salt, a hydrate or a solvate as active ingredients, and the active ingredients are mixed with a pharmaceutically acceptable carrier or an excipient to prepare a composition and prepare a clinically acceptable dosage. The compound disclosed by the invention can treat and/or prevent proliferative diseases and prostatic cancer, lung cancer and cervical cancer.
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(2017/07/22)

Quinazoline compound containing dihydroindoline and similar structure and application thereof
The invention discloses a quinazoline compound containing dihydroindoline and a similar structure. The quinazoline compound is as shown in a general formula I, wherein the general formula I is shown in the description. The quinazoline compound containing the dihydroindoline and the similar structure, and pharmaceutically acceptable salts, hydrates or solvates thereof are used as active components, and are mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition; and the composition is prepared into clinically acceptable preparations. The compound provided by the invention can be used for treating and/or preventing proliferative diseases, and treating and/or preventing prostate cancer, lung cancer and cervical cancer.
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(2017/07/22)

NOVEL FLUORINATED QUINAZOLINE DERIVATIVES AS EGFR INHIBITORS
A novel class of fluorinated derivatives of Formula (I) have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders. (I)
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Paragraph 00195

(2017/08/01)

Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors
Two series of afatinib derivatives bearing cinnamamide moiety (10a-n and 11a-h) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC50 values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC50 9.1 nM) and 10k (IC50 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC50 1.6 nM). Structure-activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn't decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.
Tu, Yuanbiao,Ouyang, Yiqiang,Xu, Shan,Zhu, Yan,Li, Gen,Sun, Chao,Zheng, Pengwu,Zhu, Wufu
p. 1495 - 1503
(2016/03/15)

6-Oxooxazolidine–quinazolines as noncovalent inhibitors with the potential to target mutant forms of EGFR
Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFRT790Mand EGFRL858Rkinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants.
Shao, Jiaan,Chen, En,Shu, Ke,Chen, Wenteng,Zhang, Guolin,Yu, Yongping
p. 3359 - 3370
(2016/07/20)

Quinazoline compound containing cinnamamide structure and preparation method and application thereof
The invention discloses a quinazoline compound containing cinnamamide structure, geometric isomers of the quinazoline compound, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the quinazoline compound, as well as a preparation method of the quinazoline compound. The invention also discloses application in the preparation of drugs for treating and/or preventing proliferative diseases, application in the preparation of drugs for treating and/or preventing cancers, and application in the preparation of drugs for treating and/or preventing prostate cancer, lung cancer and cervical cancer. Cyano groups are removed, side chains such as S-tetrahydrofuran-3-oxy, and activity for A549 has a significant increase. In-vitro antitumor activity screening for various EGFR (epidermal growth factor receptor) inhibitor highly-expressed cell strains shows high antitumor activity and selectivity, some compounds good in in-vitro antitumor activity are also selected for in-vivo activity testing of EGFR and VEGFR2/KDR. Experiments show that some compounds have efficient antitumor activity.
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(2016/12/22)

4-quinazoline amine derivatives and their use
A 4-quinazoline amine derivative as represented by formula (1), a pharmaceutical composition comprising the derivative, and an application thereof in preparing medicine for curing cancer. The cancer is a drug-resistant cancer, preferably a cancer resisting an EGFR reversible inhibitor, and more preferably, a cancer resisting gefitinib, erlotinib or lapatinib; alternatively, the cancer carries EGFR mutation.
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(2017/01/31)

QUINAZOLINE DERIVATIVE AND PREPARATION METHOD THEREFOR
The present invention relates to a quinazoline derivative shown in formula (I) and a preparation method therefor, a pharmaceutical composition comprising the compound shown in formula (I), and an application of the compound in preparing drugs for curing and preventing tumors. The compound of the present invention can irreversibly prevent EGFR phosphorylation, and effectively depress signal transduction of cancer cells, and accordingly has higher anti-tumor activity in vitro and in vivo,
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Paragraph 0077

(2016/08/17)

NOVEL FLUORINATED DERIVATIVES AS EGFR INHIBITORS USEFUL FOR TREATING CANCERS
A novel class of fluorinated derivatives of Formula I have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders.
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Paragraph 00264; 00265

(2016/09/22)

Preparation technology of Afatinib intermediate
The invention relates to a preparation technology of an Afatinib intermediate, a target intermediate is obtained easily and efficiently by using a chloro reagent and an alkali reagent, the yield is high, the cost is low, and the preparation technology is suitable for industrial production.
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Paragraph 0035; 0036

(2017/01/02)

QUINAZOLINE DERIVATIVES, COMPOSITIONS THEREOF, AND USE AS PHARMACEUTICALS
Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof,and method of use thereof.
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(2015/02/02)

Synthesis of quinazoline analogues with differential activity for HER2-overexpressing breast cancer cells
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Jang, Sun-Young,Lee, Seul,Kim, Mira,Ham, Young Jin,Cha, Mi Young,Suh, Kwee Hyun,Kim, Young Hoon,Kwon, Ara,Kang, Hae Ju,Min, Kyung Hoon,Lee, Kwang-Ok
p. 1933 - 1935
(2015/07/15)

Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors
We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
Zhang, Long,Yang, Yingying,Zhou, Haojie,Zheng, Qingmei,Li, Yuhao,Zheng, Shansong,Zhao, Shuyong,Chen, Dong,Fan, Chuanwen
p. 445 - 463
(2015/09/01)

TARGETED COVALENT PROBES AND INHIBITORS OF PROTEINS CONTAINING REDOX-SENSITIVE CYSTEINES
Covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR'2) of therapeutically important proteins (particularly kinases and phosphatases) are disclosed, where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein. Methods for synthesizing these compounds are also disclosed, as well as methods of using them for determining the bioactivity of a chemical composition comprising an active compound toward a specific protein and for determining the potency of an inhibitor against a specific protein.
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(2014/06/24)

AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
Provided herein are aminoquinazoline compounds, salts and uses thereof. The compounds have Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug ther
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Paragraph 00298-00299

(2014/11/13)

QUINAZOLINE DERIVATIVES SUBSTITUTED BY ANILINE, PREPARATION METHOD AND USE THEREOF
The invention relates to quinazoline derivatives substituted by aniline which are represented by the below formula (I), pharmaceutical acceptable salts and stereoisomer thereof, wherein these groups of R1, R2, R3, R4, R5, R6, L and n have the meanings given in the specification. The invention also relates to preparation methods, pharmaceutical compositions, pharmaceutical preparation and the use for preparation of medicine of treating excessive hyperplasia and chronic obstructive pulmonary disease and uses for treating excessive hyperplasia and chronic obstructive pulmonary disease thereof.
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(2013/07/25)

Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting EGFR
This letter describes the construction of conformationally constrained quinazoline analogues. Structure-activity relationship studies led to the identification of the lead compound 9n. Compound 9n exhibits effective in vitro activity against A431WT,overexpression and H1975 [L858R/T790M] cancer cell lines but is significantly less effective against EGFR negative cancer cell lines (SW620, A549, and K562). Compound 9n was also assessed for potency in enzymatic assays and in vivo antitumor studies. The results indicated that 9n is a potent kinase inhibitor against both wild-type and T790M mutant EGFR kinase. Meanwhile, an oral administration of 9n at a dose of 200 mg/kg produced a considerable antitumor effect in a A431 xenograft model, as compared to gefitinib. A preliminary pharmacokinetic study of 9n also indicates it has good pharmacokinetic properties, and therefore, it is a good starting point for further development.
Wu, Jianwei,Chen, Wenteng,Xia, Guangxin,Zhang, Jing,Shao, Jiaan,Tan, Biqin,Zhang, Chunchun,Yu, Wanwan,Weng, Qinjie,Liu, Haiyan,Hu, Miao,Deng, Hailin,Hao, Yu,Shen, Jingkang,Yu, Yongping
p. 974 - 978
(2013/10/22)

QUINAZOLINE DERIVATIVES AS KINASES INHIBITORS AND METHODS OF USE THEREOF
Disclosed are quinazolines of formula (I), pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
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Page/Page column 20

(2013/04/25)

SUBSTITUTED AMINOQUINAZOLINES USEFUL AS KINASES INHIBITORS
The present invention is directed to novel quinazolines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
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Page/Page column 21

(2013/12/03)

BICYCLIC COMPOUNDS AS KINASES INHIBITORS
The present invention is directed to novel bicyclic compounds, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are useful for the treatment of protein kinases mediated diseases and conditions. Novel bicyclic compounds disclosed herein include quinazolines and quinolines.
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Paragraph 0056

(2013/12/03)

QUINOLINE OR QUINAZOLINE DERIVATIVES WITH APOPTOSIS INDUCING ACTIVITY ON CELLS
Provided is a pharmaceutical composition comprising, as an active ingredient, a quinoline or quinazoline derivative of formula (I), a pharmaceutically acceptable salt, an isomer, a hydrate, and a solvate thereof, which is effective in the prevention and treatment of a cancer, inflammation, autoimmune diseases or neurodegenerative disorders which are induced by the overexpression of inhibitor of apoptosis proteins (IAPs).
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(2012/03/26)

QUINAZOLINE DERIVATIVES
Quinazoline derivatives of the following formula: wherein R1, R2, R3, R4, R5, X, Y, and Z are defined herein. It also discloses a method of treating cancer with one of these compounds.
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Page/Page column 23-24

(2010/02/17)

Modified PEG-anilinoquinazoline derivatives as potential EGFR PET agents
Inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) has emerged as a major approach for cancer-targeted therapy. Consequently, there has been a great interest in the use of labeled EGFR-TK inhibitors as positron emission tomography (P
Dissoki, Samar,Eshet, Renana,Billauer, Hana,Mishani, Eyal
scheme or table
p. 41 - 52
(2009/12/01)

Structure-based virtual screening of Src kinase inhibitors
Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC50 value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quin azolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC50 ratio > 80-fold) and VEGFR-2 (IC50 ratio > 110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC50 values of 1.52 and 0.78 μM, respectively. Moreover, compound 43 (0.1 μM) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization.
Lee, Kyungik,Kim, Jongwoo,Jeong, Ki-Woong,Lee, Ki Won,Lee, Yeonjoo,Song, Ji Yeon,Kim, Maeng Sup,Lee, Gwan Sun,Kim, Yangmee
experimental part
p. 3152 - 3161
(2009/09/27)

Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.
Hur, Wooyoung,Velentza, Anastasia,Kim, Sungjoon,Flatauer, Laura,Jiang, Xinnong,Valente, David,Mason, Daniel E.,Suzuki, Melissa,Larson, Brad,Zhang, Jianming,Zagorska, Anna,DiDonato, Michael,Nagle, Advait,Warmuth, Markus,Balk, Steven P.,Peters, Eric C.,Gray, Nathanael S.
supporting information; experimental part
p. 5916 - 5919
(2009/06/25)

Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction
In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
Kim, Young Hoon,Choi, Hojin,Lee, Jaekwang,Hwang, In-Chang,Moon, Seung Kee,Kim, Soo Jin,Lee, Hong Woo,Im, Dai Sig,Lee, Sung Sook,Ahn, Soon Kil,Kim, Sang Woong,Han, Cheol Kyu,Yoon, Jeong Hyeok,Lee, Kyung Joo,Choi, Nam Song
scheme or table
p. 6279 - 6282
(2009/07/18)