- Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors
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ATP-competitive mTOR inhibitors have been studied as potential antitumor agents. Based on the structure-activity relationship of known mTOR inhibitors, a series of novel imidazo[1,2-b]pyridazine derivatives were synthesized and characterized. The anti-proliferative activities of these compounds were evaluated by SRB assay against six human cancer cell lines. Imidazo[1,2-b]pyridazine diaryl urea derivatives A15?A24 exhibited significant anti-proliferative activity especially against non-small cell lung cancer A549 and H460 with IC50values ranging from 0.02?μM to 20.7?μM. Among them, compounds A17 and A18 showed mTOR inhibitory activity with IC50of 0.067?μM and 0.062?μM, respectively. A more detailed analysis of compounds A17 and A18 showed that they induced G1-phase cell cycle arrest and suppressed the phosphorylation of AKT and S6 at cellular level. Moreover, obvious anticancer effect of A17 in?vivo was observed in established nude mice A549 xenograft model.
- Mao, Beibei,Gao, Shanyun,Weng, Yiran,Zhang, Liangren,Zhang, Lihe
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Read Online
- HPK1 ANTAGONISTS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.
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Paragraph 1251; 1252
(2021/03/19)
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- Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease
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A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.
- Colombano, Giampiero,Caldwell, John J.,Matthews, Thomas P.,Bhatia, Chitra,Joshi, Amar,McHardy, Tatiana,Mok, Ngai Yi,Newbatt, Yvette,Pickard, Lisa,Strover, Jade,Hedayat, Somaieh,Walton, Michael I.,Myers, Stephanie M.,Jones, Alan M.,Saville, Harry,McAndrew, Craig,Burke, Rosemary,Eccles, Suzanne A.,Davies, Faith E.,Bayliss, Richard,Collins, Ian
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p. 2447 - 2465
(2019/03/17)
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- CYCLIC DI-NUCLEOTIDE COMPOUNDS AS STING AGONISTS
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A class of polycyclic compounds of general formula (I), wherein Base1, Base2, Y, Za, Xa, Xa1, Xb, Xb1, Xc, Xc1, Xd, Xd1, R1, R1a, R2, R2a, R3, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, and R9 are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.
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Paragraph 0202-0203
(2019/07/14)
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- Synthesis method of 6-cholro-8-bromoimidazole[1,2-b]pyridazine
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The invention relates to a synthesis method of 6-chloro-8-bromoimidazole[1,2-b]pyridazine. 3-amino-6-chloropyridazine, liquid bromine, and a chloroacetaldehyde water solution are taken as the raw materials, the ratio of amount of substance of 3-amino-6-chloropyridazine to liquid bromine is 1:1.0-4.5, the ratio of amount of substance of 3-amino-6-chloropyridazine to the chloroacetaldehyde water solution (40%) is 5:1.0-1:3.2; in a proper solvent, in the presence of alkali, raw materials carry out continuous reactions at a temperature of 50 to 100 DEG C to generate a coarse product of 6-cholro-8-bromoimidazole[1,2-b]pyridazine, and then the coarse product is purified to obtain purified product of 6-cholro-8-bromoimidazole[1,2-b]pyridazine. The provided synthesis method has the advantages that the raw materials are easily available, the prices are reasonable, at the same time, no heavy metal or corrosive gas is used in the preparation reactions, the reactions are mild, there is no special requirement on reaction equipment, the product can be produced by common corrosion resistant equipment, and the reaction conditions are moderate.
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Paragraph 0027
(2017/01/02)
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- 6-aryl substituted-imidazo-[ 1,2-b] pyridazine derivatives, their preparation and use
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The invention discloses a 6-aryl-substituted-imidazole-[1,2-b]pyridazine derivative and a preparation method thereof and application of the derivative in inhibition of tumors. The 6-aryl-substituted-imidazole-[1,2-b]pyridazine derivative provided by the invention is represented by a general formula (I), and substituent groups in the general formula are specifically defined in the specification. The derivative can inhibit growth of tumor cells in the G1 phase, exerts inhibitory effects on a lung cancer, a breast cancer, glioma and melanoma and has an obvious inhibitory effect on transplanted human lung tumors in nude mice.
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Paragraph 0026; 0123; 0138; 0139; 0140
(2016/10/07)
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- IMIDAZOPYRIDAZINE COMPOUNDS
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The present invention relates to the use of novel compounds of formula I: wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.
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Paragraph 0227-0228
(2013/05/09)
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- IMIDAZOPYRIDAZINE COMPOUNDS
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The present invention relates to the use of novel compounds of formula (I): wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 51
(2013/05/22)
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- TRICYCLIC HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
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There is provided compounds of formula (I), wherein R1, R2, X, R3 and R4 have meanings given in the description (and which compounds are optionally substituted as indicated in the description), and pharmaceutica
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Page/Page column 71
(2013/03/26)
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- BICYCLIC PIPERAZINE COMPOUNDS
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Bicyclic piperazine compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Paragraph 0242
(2013/05/21)
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- Rational design of highly selective spleen tyrosine kinase inhibitors
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A novel approach to design selective spleen tyrosine kinase (Syk) inhibitors is described. Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of autoimmune diseases such as asthma, rheumatoid arthritis, and SLE. Fostamatinib, a Syk inhibitor that successfully completed phase II clinical trials, also exhibits some undesirable side effects. More selective Syk inhibitors could offer safer, alternative treatments. Through a systematic evaluation of the kinome, we identified Pro455 and Asn457 in the Syk ATP binding site as a rare combination among sequence aligned kinases and hypothesized that optimizing the interaction between them and a Syk inhibitor molecule would impart high selectivity for Syk over other kinases. We report the structure-guided identification of three series of selective spleen tyrosine kinase inhibitors that support our hypothesis and offer useful guidance to other researchers in the field.
- Lucas, Matthew C.,Goldstein, David M.,Hermann, Johannes C.,Kuglstatter, Andreas,Liu, Wenjian,Luk, Kin Chun,Padilla, Fernando,Slade, Michelle,Villase?or, Armando G.,Wanner, Jutta,Xie, Wenwei,Zhang, Xiaohu,Liao, Cheng
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supporting information
p. 10414 - 10423
(2013/02/22)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Page/Page column 80
(2012/05/21)
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- IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
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The present invention relates to novel imidazo[1,2-b]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.
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Page/Page column 69
(2011/05/11)
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- IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AND THEIR USE AS PDE10 INHIBITORS
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The present invention relates to novel imidazo[1,2-b]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE10) and which are useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, to the use of such compounds or pharmaceutical compositions for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases.
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Page/Page column 29
(2011/11/12)
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- IMIDAZOPYRIDAZINYL COMPOUNDS AND THEIR USES FOR CANCER
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Disclosed are imidazopyridazinyl compounds of Formula (I): (I), or pharmaceutically salts and prodrugs thereof, wherein R3 is C2-4alkenyl or a cyclic group, and R1 and R2 are defined herein. Also disclosed are methods of using such compounds in the treatment of at least one CYP17 associated condition, such as, for example, cancer, and pharmaceutical compositions comprising such compounds.
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Page/Page column 30
(2011/11/13)
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