- Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors
-
‘precision medicine’ is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.
- Cai, Shi,Li, Pei,Sun, Minghao,Zhang, Fangqing,Zhang, Huibin,Zhou, Jinpei
-
-
Read Online
- Discovery of potent colony-stimulating factor 1 receptor inhibitors by replacement of hinge-binder moieties
-
Tumor-associated macrophages (TAMs) are predominantly associated with tumor growth. Colony-stimulating factor 1 receptor (CSF1R) acts as a key regulator of TAM survival and differentiation and is a molecular target for cancer therapies. Herein, novel CSF1
- Lee, Jung Wuk,Park, Jiwon,Kim, Jina,Kim, Jihyung,Choi, Changyu,Min, Kyung Hoon
-
-
- Macrocyclic kinase inhibitor and application thereof
-
The invention belongs to the technical field of medicines, in particular to a macrocyclic tyrosine kinase inhibitor compound, pharmaceutically acceptable salt, ester and stereoisomer of the macrocyclic tyrosine kinase inhibitor compound. More specifically, the tyrosine kinase is one or more of TRK, ALK and ROS1; the present invention relates to a compound, a pharmaceutically acceptable salt thereof, an ester thereof, a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a method for preparing the compound, the pharmaceutically acceptable salt thereof,the ester thereof, and the stereoisomer thereof, and uses of the compound, the pharmaceutically acceptable salt thereof, the ester thereof, and the stereoisomer thereof.
- -
-
Paragraph 0161-0164
(2020/09/08)
-
- Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma
-
Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure?activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell–like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.
- Chen, Yun,Bai, Gang,Ning, Yi,Cai, Shi,Zhang, Tao,Song, Peiran,Zhou, Jinpei,Duan, Wenhu,Ding, Jian,Xie, Hua,Zhang, Huibin
-
-
- Imidazopyridazine IRAK4 inhibitor, and preparation method and application thereof
-
The invention belongs to the field of medicines, and especially relates to an imidazopyridazine compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, and an applicationof a medicinal composition of the compound or the salt in the treatment of tumors, inflammations, immunity and other diseases. The imidazopyridazine compound is a novel protein kinase IRAK4 inhibitor, and can selectively inhibit IRAK4 and downstream signaling pathways thereof. The compound has the structural formula I.
- -
-
Paragraph 0090; 0091; 0092
(2018/03/26)
-
- Convenient two-step one-pot synthesis of 3-substituted imidazo[1,2-a]pyridines and imidazo[1,2-b]pyridazines
-
Abstract: A convenient and novel two-step one-pot method for the synthesis of 3-substituted imidazo[1,2-a]pyridines and 3-substituted imidazo[1,2-b]pyridazines was developed through the reaction of heterocyclic amines and N,?N-dimethylformamide dimethyl a
- Fan, Hongli,Li, Fenghai
-
-
- Synthetic method of 6-chloroimidazo [1, 2-b]pyridazine-3-formic acid
-
The invention relates to a synthetic method of 6-chloroimidazo [1, 2-b]pyridazine-3-formic acid. The synthetic method comprises the steps of reacting N,N-dimethylformamide dimethyl acetal and 3-amino-6-chloropyridazine at the temperature of 40 to 120 DEG C to obtain an intermediate; under an alkali action, reacting at the temperature of 65 to 140 DEG C, and carrying out rotary evaporation and concentration to obtain a 6-chloroimidazo [1,2-b]pyridazine-3-formic acid ethyl ester crude product; recrystallizing the crude product to obtain a pure product; under an alkali action, carrying out hydrolysis reaction in a certain solvent, finishing reaction, neutralizing through hydrochloric acid, carrying out suction filtration, and washing drying to obtain a 6-chloroimidazo [1, 2-b]pyridazine-3-formic acid pure product. The synthetic method provided by the invention is adopted for preparing the 6-chloroimidazo [1, 2-b]pyridazine-3-formic acid, so that the reaction raw materials can be obtained easily, the method is easy to operate and control and simple in aftertreatment, and the product has stable quality and high purity.
- -
-
Paragraph 0015; 0016; 0018; 0020; 0022; 0024; 0026; 0028
(2017/08/29)
-
- IMIDAZOPYRIDAZINE COMPOUNDS USEFUL AS MODULATORS OF IL-12, IL-23 AND/OR IFN ALPHA RESPONSES
-
Compounds of formula I or a stereoisomer or pharmaceutically-acceptable salt thereof, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.
- -
-
Page/Page column 85
(2017/07/14)
-
- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
-
Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
-
supporting information
p. 8267 - 8276
(2017/06/27)
-
- SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
-
Provided herein are novel substituted bicyclic aza-heterocycle sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
- -
-
Paragraph 0241; 0242
(2017/04/04)
-
- 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.
- -
-
Page/Page column 347; 348
(2016/04/26)
-
- IMIDAZOPYRIDAZINE KINASE INHIBITORS USEFUL TO TREATING A DISEASE OR DISORDER MEDIATED BY AAK1, SUCH AS ALZHEIMER'S DISEASE, BIPOLAR DISORDER, PAIN, SCHIZOPHRENIA
-
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
- -
-
Page/Page column 45
(2015/03/13)
-
- 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.
- -
-
Page/Page column 69
(2015/02/19)
-
- 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.
- -
-
Paragraph 00641
(2014/10/04)
-
- SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
-
Provided herein are novel substituted bicyclic aza-heterocycle sirtuin- modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin- modulating compound in combination with another therapeutic agent.
- -
-
Page/Page column 75
(2013/05/09)
-
- COMPOUNDS AND COMPOSITIONS AS TRK INHIBITORS
-
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase activity.
- -
-
-
- IMIDAZOPYRIDAZINES FOR USE AS PROTEIN KINASE INHIBITORS
-
There is provided compounds of formula (I): wherein Z, M, R1, X, R3, R4 and R5 have meanings given in the description, an pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protei kinase (e.g. a PIM family kinase or PI3-K) is desired and/or required, an particularly in the treatment of cancer.
- -
-
Page/Page column 59
(2009/06/27)
-
