cas 853908-50-6, 6-Bromo-3-nitro-4-quinolinol

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Compound serving as Hippo signal channel inhibitor
The invention provides a compound represented by a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The compound disclosed by the invention has an inhibiting effecton a Hippo signal channel, and can be used for preparing a Hippo signal channel inhibitor. Meanwhile, cell proliferation can be promoted by inhibiting a Hippo signal channel, regeneration of damagedorgans is facilitated, particularly regeneration of damaged liver tissues can be promoted, and acute liver injury can be effectively repaired. Therefore, the compound provided by the invention can also be used for preparing medicines for treating various diseases related to the Hippo signal channel, such as medicines beneficial to regeneration of damaged organs, particularly medicines beneficial to regeneration of damaged liver tissues, and medicines for repairing acute liver injury. The compound can be used for medication research in the field of organ regeneration.
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(2020/12/31)

Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors
PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.
Bahekar, Rajesh,Dave, Bhushan,Soman, Shubhangi,Patel, Dipam,Chopade, Rajendra,Funde, Radhika,Kumar, Jeevan,Sachchidanand,Giri, Poonam,Chatterjee, Abhijit,Mahapatra, Jogeswar,Vyas, Purvi,Ghoshdastidar, Krishnarup,Bandyopadhyay, Debdutta,Desai, Ranjit C.
supporting information
p. 1313 - 1319
(2019/04/13)

Discovery of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo signaling pathway inhibitors
Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF). Structure-activity relationship (SAR) of these compounds was also discussed. The most potent compound in the A549-CTGF cell assay, 11g, was then evaluated by real-time PCR and immunofluorescence assays. Overall, this study provides a starting point for later drug discovery targeting the Hippo signaling pathway.
Chen, Pei,Li, L.,Lin, Guifeng,Qiao, Jingxin,Xia, A.,Xiang, Z.,Yang, Shengyong,Zhang, Guo
(2019/08/12)

1H-[1,2,3]triazolo[4,5-c]quinoline derivative, preparation method and uses thereof
The invention belongs to the field of chemical medicine, particularly relates to a 1H-[1,2,3]triazolo[4,5-c]quinoline derivative, a preparation method and uses thereof, and provides a 1H-[1,2,3]triazolo[4,5-c]quinoline derivative, which has a structure represented by a formula I. The invention further provides a preparation method and uses of the 1H-[1,2,3]triazolo[4,5-c]quinoline derivative. Theformula I is defined in the specification.
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Paragraph 0274; 0275; 0278; 0279

(2018/09/28)

Design, synthesis and biological evaluation of novel phenylsulfonylurea derivatives as PI3K/mTOR dual inhibitors
Five series of novel phenylsulfonylurea derivatives, 19a–d, 20a–d, 21a–d, 22a–d and 23a–d, bearing 4-phenylaminoquinoline scaffold were designed, synthesized and their IC50 values against four cancer cell lines (HepG-2, A549, PC-3 and MCF-7) were evaluated. Most compounds showed moderate cytotoxicity activity against the cancer cell lines. Structure–activity relationships (SARs) and pharmacological results indicated that introduction of 4-aminoquinoline scaffold and phenylsulfonylurea scaffold were beneficial for anti-tumor activity. Moreover, para-methoxyl substitution of 4-anilino moiety and para-halogen substitution of phenylsulfonylurea have different impacts on different series of compounds. Furthermore, the micromolecule group substitution in the 6-position of the quinoline ring have a slight impact on the cellular activity of the target compounds.
Zhao, Bingbing,Lei, Fei,Wang, Caolin,Zhang, Binliang,Yang, Zunhua,Li, Wei,Zhu, Wufu,Xu, Shan
(2018/07/13)

Design, synthesis, and antitumor evaluation of quinoline-imidazole derivatives
A series of compounds bearing quinoline-imidazole (8a–e, 9a–e, 10a–e, 11a–e, and 12a–e) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC-3, HepG2, and MCF-7 cells by the MTT method, with NVP-BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC-3 cells, with half-maximal inhibitory concentration (IC50) values of 2.42 ± 1.02 μM, 6.29 ± 0.99 μM, and 5.11 ± 1.00 μM, respectively, which was equal to NVP-BEZ235 (0.54 ± 0.13 μM, 0.36 ± 0.06 μM, 0.20 ± 0.01 μM). Besides, the IC50 value of 12a against the cell line WI-38 (human fetal lung fibroblasts) was 32.8 ± 1.23 μM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K-Akt-mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP-BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C-6 of the quinoline ring was replaced by a bromine atom.
Xiao, Zhen,Lei, Fei,Chen, Xiuying,Wang, Xiaolei,Cao, Lujie,Ye, Kejun,Zhu, Wufu,Xu, Shan
(2018/05/14)

Sulfonylurea compound as well as preparation method and application thereof
The invention discloses a sulfonylurea compound, geometrical isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, and a preparation method thereof. The sulfonylurea compound, the pharmaceutically acceptable salts, hydrates or solvates serving as active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare compositions and preparedinto clinically acceptable dosage forms. The invention further discloses application of the compounds in preparation of medicines for treating and/or preventing proliferative diseases, application inpreparation of medicines for treating and/or preventing cancers, and application in preparation of medicines for treating and/or prostatic cancer, lung cancer and breast cancer.
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(2018/09/14)

Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers
Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC50 value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.
Sun, Qi-Zheng,Lin, Gui-Feng,Li, Lin-Li,Jin, Xi-Ting,Huang, Lu-Yi,Zhang, Guo,Yang, Wei,Chen, Kai,Xiang, Rong,Chen, Chong,Wei, Yu-Quan,Lu, Guang-Wen,Yang, Sheng-Yong
p. 6337 - 6352
(2017/08/02)

As the PI3K/mTOR inhibitor compound, its preparation and use
The invention discloses a compound used as a PI3K/mTOR inhibitor, which is a compound with a general formula of (IA) or (IB), wherein R1 is selected from hydrogen, halogen, alkyl, alkyloxy, and amido, or forms a fused ring with R2; R2 is selected from hydrogen, amido, sulfamine, sulfonylurea, alkyl, and alkyloxy, or forms a fused ring with R1; R3 is selected from hydrogen, and C1-C6 alkyl; R4 is selected from hydrogen, amido, acylamino, or sulfamine; R5 is selected from hydrogen, halogen, alkyl or alkyloxy. The invention also discloses a preparation method of the compound used as a PI3K/mTOR inhibitor, and an application of the compound as a drug in treating PI3K/mTOR related diseases, especially PI3K/mTOR related cancers.
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Paragraph 0189; 0191

(2017/05/20)

Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
The present invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth.
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(2016/04/26)

Novel quinoline-derived mTOR inhibitors with remarkable enzymatic and cellular activities: Design, synthesis and biological evaluation
Herein, we reported the preparation and in vitro development of a novel series of quinoline-based mTOR inhibitors, some of which were obtained via introducing a ring-opening strategy. As for enzymatic activity, more than half of these quinoline derivatives exhibited moderate to potent inhibition against mTOR. Among them, six compounds showed IC50 values below 50 nM. In particular, several quinolines exhibited remarkably enhanced anti-proliferative activities against all the three tested tumor cell lines in contrast to the initial lead 9. As a representative in this series, compound 24 demonstrated IC50 values of 0.11, 0.17 and 0.04 μM against HCT-116, PC-3 and MCF-7 cell lines, respectively. Besides, compounds 17 and 24 were identified to be selective over class I PI3Ks. Further Western blot analysis validated the dual inhibition of mTORC1 and mTORC2 as a result of compound 24 treatment in the MCF-7 cell line, which was beneficial for conquering the S6K/IRS1/PI3K negative feedback loop. Moreover, acceptable stability was displayed by compound 17, another representative of this series, in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), as well as rat liver microsome (RLM). By virtue of the favorable biological profiles, several quinolines merit further in vivo investigation.
Ma, Xiao-Dong,Qiu, Ni,Yang, Bo,He, Qiao-Jun,Hu, Yong-Zhou
p. 297 - 310
(2016/03/01)

Morphline and quinoline compound, preparation method thereof, and use thereof
The invention discloses a morpholinoquinoline compound represented by a formula (I) which is shown in the description, wherein the R1 represents a C1-C6 alkyl group, an aryl group, an amino group, a C3-C10 cycloalkyl group, a heterocyclic radical, or a heteroaryl group; the R2 represents H, a halogen element, or -OR10; the R3 represents H, -NHR10, or -NHC(=O)R10; the R4 represents H, a C1-C6 alkyl group, -C(=O)R10, or -S(=O)2R10; the R5 and R6 individually represent H, a C1-C6 alkyl group, or a halogen element; the R7 and R8 individually represent H, a C1-C6 alkyl group, or a halogen element, or the R7 and R8 can be emerged as =O; the R9 represents H, a C1-C6 alkyl group, -OR10, or a halogen element; the R10 represents H, a C1-C6 alkyl group, a C3-C10 cycloalkyl group, an aryl group, or a heteroaryl group; the alkyl groups, alkoxyl groups, aryl groups, and heteroaryl groups mentioned above in R1 to R10 can be optionally replaced by one or more groups, and these groups can be alkyl group, alkenyl group, alkynyl group, halogen elements, alkoxyl group, aryl group, heteroaryl group, amino group, cyan group, nitro group, carboxyl group, ester group, carbamyl group, sulfonyl group, sulfamic group, or the like. The morpholinoquinoline compound can be used as a drug to treat diseases related with PI3K/mTOR.
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Paragraph 0170; 0172

(2016/10/07)

KETONE DERIVATIVES OF IMIDAZOLES, PHARMACEUTICAL COMBINATIONS AND USES THEREOF
This application relates to ketone compounds of imidazoles, pharmaceutically acceptable salts, solvents, polymorphs or prodrugs thereof, and further relates to pharmaceutical combinations comprising the foregoing substances and uses for preventing and treating protein kinase related diseases such as cancer, metabolic diseases, and cardiovascular diseases.
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Paragraph 0071; 0073

(2016/10/06)

Imidazole derivatives, its pharmaceutical composition and use thereof
Imidazolone compounds, pharmaceutically acceptable salts, solvates, polymorphs or prodrugs thereof are disclosed. Pharmaceutical compositions comprising above substances and uses for preventing and treating protein kinases related diseases, such as cancers, metabolic diseases, cardiovascular diseases and the like, are also disclosed.
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Paragraph 0195-0196

(2017/02/24)

JAK PI3K/mTOR combination therapy
Provided herein is a combination therapy comprising a JAK kinase inhibitor and a dual PI3K/mTOR inhibitor, as well as methods of treating various cancers through the use of such a combination therapy.
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Page/Page column 18

(2016/06/28)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or a receptor tyrosine kinase (RTK) in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase α and/or an RTK in a subject. In yet another aspect, a method of inhibiting phosphorylation of Akt (S473) in a cell is set forth.
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(2015/02/19)

HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
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(2015/11/30)

COMBINATION OF KINASE INHIBITORS AND USES THEREOF
The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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(2014/10/04)

Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents
In this research, a series of 4-(1,2,3-triazol-1-yl)coumarin conjugates were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines, including human breast carcinoma MCF-7 cell, colon carcinoma SW480 cell and lung carcinoma A549 cell. To increase the biological potency, structural optimization campaign was conducted focusing on the C-4 position of 1,2,3-triazole and the C-6, C-7 positions of coumarin. In addition, to further evaluate the role of 1,2,3-triazole and coumarin for antiproliferative activity, 9 compounds possessing 4-(piperazin-1-yl)coumarin framework and 3 derivatives baring quinoline core were also synthesized. By MTT assay in vitro, most of the compounds display attractive antitumor activities, especially 23. Further flow cytometry assays demonstrate that compound 23 exerts the antiproliferative role through arresting G2/M cell-cycle and inducing apoptosis.
Zhang, Wenjuan,Li, Zhi,Zhou, Meng,Wu, Feng,Hou, Xueyan,Luo, Hao,Liu, Hao,Han, Xuan,Yan, Guoyi,Ding, Zhenyu,Li, Rui
supporting information
p. 799 - 807
(2014/02/14)

JAK P13K/mTOR COMBINATION THERAPY
Provided herein is a combination therapy comprising a JAK kinase inhibitor and a dual PBK/mTOR inhibitor, as well as methods of treating various cancers through the use of such a combination therapy.
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Page/Page column 27

(2013/03/26)

HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
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(2012/09/11)

SUBSTITUTED IMIDAZOQUINOLINE DERIVATIVES AS KINASE INHIBITORS
The present invention relates to substituted imidazo[4,5-c]quinoline derivatives, the compounds of formula (I), wherein R1 R2, R3, R4, R5, R6 and R7 are as defined in the specification, processes for their preparation, pharmaceutical compositions comprising compounds of formula (I), and their use in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer. These compounds can also be used in the treatment of inflammatory diseases and angiogenesis related disorders.
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Page/Page column 47

(2012/02/02)

SUBSTITUTED IMIDAZOQUINOLINE DERIVATIVES
The present invention relates to substituted imidazo[4,5-c]quinoline derivatives of formula (I), wherein R1, R2 and R3 are as defined in the specification, processes for their preparation, pharmaceutical compositions comprising compounds of the present invention and their use in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer. These compounds can also be used in the treatment of inflammation and angiogenesis related disorders.
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Page/Page column 42

(2012/06/30)

IMIDAZO [4,5-C]QUINOLINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF TUMORS AND/OR INFLAMMATION
The present invention provides the compounds of formula (I): The present invention relates to imidazo[4,5-c]quinoline derivatives of formula (I), process for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases mediated by phosphatidylinositol-3-kinase (PBK) and/or mammalian target of rapamycin (mTOR) and/or tumor necrosis factor-α (TNF-oc) and/or interleukin-6 (IL-6), particularly in the treatment of cancer and inflammation.
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Page/Page column 15

(2012/05/07)

IMIDAZO [4,5-C]QUINOLINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF TUMORS AND/OR INFLAMMATION
The present invention provides the compounds of formula (I): (I) The present invention relates to imidazo[4,5-c]quinoline derivatives of formula (I), process for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases mediated by phosphatidylinositol-3-kinase (PBK) and/or mammalian target of rapamycin (mTOR) and/or tumor necrosis factor-α (TNF-oc) and/or interleukin-6 (IL-6), particularly in the treatment of cancer and inflammation.
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Page/Page column 37-38

(2011/02/24)

PHOSPHATIDYLINOSITOL 3 KINASE INHIBITORS
Provided are compounds according to Formula (I), or stereoisomer, prodrug, polymorph, or pharmaceutically acceptable salt forms thereof, wherein X, Y, R1, R6 , R7, and R8 are as defined, which compounds are effective inhibitors of PI3-kinase and/or other medically and clinically relevant kinases. Also provided are pharmaceutical compositions and methods of using the compounds and compositions as PB -kinase and kinase inhibitors. More particularly, the compounds of the invention provide treatments and therapeutics for human diseases regulated by, or associated with, the activity of, PI3-kinases and/or protein kinases, or mutant or variant forms thereof.
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Page/Page column 141

(2010/01/12)

SALTS AND CRYSTALL FORMS OF 2-METHYL-2-[4-(3-METHYL-2-OXO-8-QUINOLIN-3-YL-2,3-DIHYDRO-IMIDAZO[4,5-C]QUINOLIN-1-YL)-PHENYL]-PROPIONITRILE
The invention relates to particular crystalline forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, its hydrates and solvates, its salts and hydrates and solvates of its salts, certain processes for their preparation, pharmaceutical compositions containing these crystalline forms, and their use in diagnostic methods or, preferably, for the therapeutic treatment of warm-blooded animals, especially humans, and their use as an intermediate or for the preparation of pharmaceutical preparations for use in diagnostic methods or, preferably, for the therapeutic treatment of warm-blooded animals, especially humans.
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Page/Page column 17

(2008/12/05)

IMIDAZOQUINOLINES AS LIPID KINASE INHIBITORS
The invention relates to novel organic compounds of formula (I) processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof - alone or in combination with one or more other pharmaceutically active compounds - for the treatment of an inflammatory or obstructive airway disease, such as asthma, disorders commonly occurring in connection with transplantation, or a proliferative disease, such as a tumor disease.
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(2008/06/13)

1H-IMIDAZO[4,5-C]QUINOLINE DERIVATIVES IN THE TREATMENT OF PROTEIN KINASE DEPENDENT DISEASES
The invention relates to the use of imidazoquinolines and salts thereof in the treatment of protein kinase diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, imidazoquinolines for use in the treatment of protein kinase dependent diseases, a method of treatment against said diseases, comprising administering the imidazoquinolines to a warm-blooded animal, especially a human, pharmaceutical preparations comprising an imidazoquinoline, especially for the treatment of a protein kinase dependent disease, novel imidazoquinolines, and a process for the preparation of the novel imidazoquinolines.
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Page/Page column 63

(2010/02/12)

1H-IMIDAZOQUINOLINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
The invention relates to imidazoquinolines of formula (I) for use in the treatment of protein kinase dependent diseases; pharmaceutical preparations comprinsing an imidazoquinoline, especially for the treatment of a pretein kinase dependent disease; novel imidazoquinolines; and a process for the preparation of the novel imidazoquinilines.
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Page/Page column 53

(2010/02/12)