- Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate
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A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
- Chen, Tao,Fang, Wei-Rong,Huang, Wei,Li, Yun-Man,Liu, Peng-Fei,Zhuo, Lin-Sheng
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- Heterocyclic compound, preparation method and application thereof
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The invention relates to a heterocyclic compound in the technical field of medicines. The compound is represented by a structural general formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, X, Y, Z, Cy1, Cy2, m, n and t have the meanings given in the specification; in addition, the invention also discloses an application of the compound and the pharmaceuticallyacceptable salt thereof in preparation of drugs for treating diseases caused by abnormal high expression of tyrosine kinase, especially application in preparation of drugs for treating and preventingcancers.
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- CARBAMATE AND UREA COMPOUNDS AS MULTIKINASE INHIBITORS
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The present disclosure describes carbamate and urea compounds as novel multikinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such multikinase inhibitors and methods of using them for treating cancer, infectious diseases, and other disorders associated with kinases are also described.
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- Preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline
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The invention discloses a preparation method of 7-benzyloxy-6-methoxy-4-hydroxyquinoline. The method comprises the following steps: under the action of anhydrous p-methylbenzenesulfonic acid, carrying out condensation reaction on 3-benzyloxy-4-methoxyanil
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Paragraph 0049; 0050; 0057; 0058; 0059
(2017/08/31)
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- A alkyne generation quinoline derivatives and its preparation and use
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The invention discloses alkynylquinoline derivatives, and a preparation method and application thereof. The acetylenoquinoline derivatives are alkynylquinoline compounds as shown in a general formula I which is described in the specification and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof. The invention also provides the preparation method for the derivatives and relates to inhibition activity of the compounds as shown in the formula I to a variety of protein tyrosine kinases (e.g. C-Met and VEGFR). Thus, the compounds can be used as anticancer drugs for treatment of human cancers.
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Paragraph 0118; 0119
(2017/08/25)
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- Naphthyridine compound and pharmaceutical composition as well as applications thereof
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The invention relates to the field of biological medicines and discloses a naphthyridine compound and a pharmaceutical composition as well as applications thereof. The naphthyridine compound has a structure shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, hydrate, solvate, metabolite, a pharmaceutically acceptable salt or a prodrug. The naphthyridine compound disclosed by the invention has an anti-tumor effect which is obviously superior to the anti-tumor effect of the prior art. And moreover, the naphthyridine compound disclosed by the invention can treat diseases mediated by protein kinase.
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Paragraph 0080; 0081; 0088; 0089
(2017/08/02)
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- Quinoline or quinazoline derivatives as well as preparation method and application thereof
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The invention relates to quinoline or quinazoline derivatives as well as a preparation method and an application thereof, namely, the quinoline or quinazoline derivatives shown as the formula I as well as pharmaceutically acceptable salts and hydrates or prodrugs of the quinoline or quinazoline derivatives. The structure is shown in the specification, wherein A1, A2, R1, R2, R3, R4, R5, R6, X, Y, Z, M, W, Cy1, Cy2, m and n are defined in the specification. The invention further relates to the function of the compounds in the general formula I for inhibiting MET kinase and the application of the compounds as well as the pharmaceutically acceptable salts and hydrates of the compounds in preparation of drugs for treating diseases caused by abnormal high expression of the MET kinase, in particular to the application in preparation of drugs for treating and preventing cancer.
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Paragraph 0233; 0234
(2017/04/11)
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- Aryloxy quinoline derivatives and their use in therapy
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Disclosed herein are aryloxy quinolines derivatives,and the said compounds are compounds of formula (I) or pharmaceutically acceptable salts thereof or solvates, wherein R1, R2, R3, R4, m, n, X, Z, Ar are defined detailedly in the description. Furthermore, medicaments comprising said compounds or salts as active components and the use for treating conditions and disorders relating to protein-tyrosine kinase receptors, especially c-Met, VEGFR are also described.
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Paragraph 0113; 0114; 0124; 0125; 0126
(2016/10/08)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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Described herein are compounds of Formula (I) or Formula (VI), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of Formula (I) or Formula (VI) and pharmaceutical compositions thereof that are mucus penetrating. Methods of using the compounds or pharmaceutical compositions thereof for treating diseases are also provided.
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- SUBSTITUTED QUINOLINE COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted quinoline compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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- QUINOLINYLOXYPHENYLSULFONAMIDES
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The present invention relates to quinolinyloxyphenylsulfonamides and stereoisomeric forms, solvates, hydrates and/or pharmaceutically acceptable salts of these quinolinyloxyphenylsulfonamide compounds as well as pharmaceutical compositions containing at least one of these compounds together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said quinolinyloxyphenylsulfonamides are useful for prophylaxsis, treatment and/or after-treatment of hyperproliferative disorders, such as cancer, tumors and particularly cancer metastases.
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Page/Page column 49; 50
(2011/05/05)
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- Met kinase inhibitors
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The present invention is directed to compounds that are useful for treating cancer having one of the following Formulas:
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Page/Page column 16
(2010/11/26)
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- C-MET MODULATORS AND METHODS OF USE
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The present invention provides compounds, which have activity for modulating protein kinase enzymatic activity and are potentially useful for modulating cellular activities such as, e.g., proliferation, differentiation, programmed cell death, migration and chemoinvasion. The present invention also provides compositions containing such compounds, and methods for producing and using such compounds and compositions.
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- C-MET MODULATORS AND METHODS OF USE
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The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.
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- Quinoline derivatives inhibiting the effect of growth factors such as VEGF
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Compounds of the formula (I): wherein: R2represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; n is an integer from 0 to 5; Z represents —O—, —NH—, —S— or —CH2—; G1represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group; Y1, Y2, Y3and Y4each independently represents carbon or nitrogen; R1represents fluoro or hydrogen; m is an integer from 1 to 3; R3represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, —NR4R5(wherein R4and R5, can each be hydrogen or C1-3alkyl), or a group R6—X1— wherein X1represents —CH2— or a heteroatom linker group and R6is an alkyl, alkenyl or alkynyl chain optionally substituted by for example hydroxy, amino, nitro, alkyl, cycloalkyl, alkoxyalkyl, or an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, which alkyl, alkenyl or alkynyl chain may have a heteroatom linker group, or R6is an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans, processes for the preparation of such derivatives, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula I. The compounds of formula I and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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Page column 40
(2010/02/08)
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- QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES
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An object of the present invention is to provide compounds which have antitumor activity and do not change cytomorphosis. Disclosed are compounds represented by formula (I) and a pharmaceutically acceptable salts and solvates thereof and pharmaceutical compositions comprising said compounds: wherein X and Z each independently represent CH or N; R1 to R3 represent H, substituted alkoxy, unsubstituted alkoxy or the like; R4 represents H; R5 to R8 represent H, halogen, alkyl, alkoxy, alkylthio, nitro, or amino, provided that R5 to R8 do not simultaneously represent H; R9 and R10 represent H, alkyl, or alkylcarbonyl; and R11 represents alkyl, alkenyl, alkynyl, or aralkyl.
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