- AROMATIC DERIVATIVES, PREPARATION METHODS, AND MEDICAL USES THEREOF
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The present disclosure relates generally to aromatic derivatives that are inhibitors of FGFR4 and are useful in treating FGFR4-associated diseases or conditions. Compositions containing the compounds of the present disclosure are also provided.
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Paragraph 0218
(2020/09/19)
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- Design, synthesis and biological evaluation of pyridone–aminal derivatives as MNK1/2 inhibitors
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Excessive phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) plays a major role in the dysregulation of mRNA translation and the activation of tumor cell signaling. eIF4E is exclusively phosphorylated by mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) on Ser209. So, MNK1/2 inhibitors could decrease the level of p-eIF4E and regulate tumor-associated signaling pathways. A series of pyridone–aminal derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against hematologic cancer cell lines. In particular, compound 42i (MNK1 IC50 = 7.0 nM; MNK2 IC50 = 6.1 nM) proved to be the most potent compound against TMD-8 cell line with IC50 value of 0.91 μM. Furthermore, 42i could block the phosphorylation level of eIF4E in CT-26 cell line, and 42i inhibited the tumor growth of CT-26 allograft model significantly. These results indicated that compound 42i was a promising MNK1/2 inhibitor for the potent treatment of colon cancer.
- Yuan, Xinrui,Wu, Hanshu,Bu, Hong,Zheng, Peiyuan,Zhou, Jinpei,Zhang, Huibin
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p. 1211 - 1225
(2019/02/28)
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- SUBSTITUTED 2-AZABICYCLO[3.1.1]HEPTANE AND 2-AZABICYCLO[3.2.1]OCTANE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS
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There is provided a compound of formula (I), wherein L1 to L3, R1 to R4, X, A and B have meanings given in the description, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which compounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor, and thus, in particular, in the treatment or prevention of inter alia substance dependence, addiction, anxiety disorders, panic disorders, binge eating, compulsive disorders, impulse control disorders, cognitive impairment and Alzheimer's disease.
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Page/Page column 126
(2019/03/17)
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- 2-AZABICYCLO[3.1.1] DERIVATIVES AS ANTAGONISTS OF THE OREXIN-1 AND OREXIN-2 RECEPTORS
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There is provided a compound of formula I, wherein L1, R1, R2, R5, X, A and B have meanings given in the description, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which compounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor, and thus, in particular, in the treatment or prevention of inter alia substance dependence, addiction, anxiety disorders, panic disorders, binge eating, compulsive disorders, impulse control disorders, cognitive impairment and Alzheimer's disease.
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Page/Page column 77
(2019/05/15)
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- COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR
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Compounds of Formula (I) or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein A, J, R1, R2, R3, R4, R5, R6, R7, R9, X, m and n are as described herein, compositions thereof, and methods and uses thereof.
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Paragraph 0359
(2017/02/24)
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- Design and synthesis of novel 3-sulfonylpyrazol-4-amino pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors
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Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate.
- Zhang, Peilong,Dong, Jiaqiang,Zhong, Boyu,Zhang, Deyi,Yuan, Hongbin,Jin, Can,Xu, Xiangyuan,Li, Hailong,Zhou, Yong,Liang, Zhi,Ji, Minghua,Xu, Tao,Song, Guowei,Zhang, Ling,Chen, Gang,Meng, Xuejing,Sun, Desheng,Shih, Joe,Zhang, Ruihao,Hou, Guojun,Wang, Chengcheng,Jin, Ying,Yang, Qiong
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p. 1910 - 1918
(2016/04/09)
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- PYRROLOTRIAZINE INHIBITORS OF IRAK4 ACTIVITY
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The present invention relates to pyrrolotriazine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.
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Page/Page column 36; 37
(2016/09/26)
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- Methylation of 4-nitro-3(5)-pyrazolecarboxylic acid
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Reactions of 4-nitro-3(5)-pyrazolecarboxylic acid dipotassium salt with different methylating agents in various solvents have been investigated to improve the synthesis of isomeric 1-methyl-4-nitro-3- and -5-pyrazolecarboxylic acids.
- Regiec, Andrzej,Mastalarz, Henryk,Mastalarz, Agnieszka,Kochel, Andrzej
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experimental part
p. 2624 - 2627
(2009/08/09)
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- Pyrazole Compound
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The present invention provides a pyrazole compound represented by the formula (I): wherein ring A0 is a pyrazole ring optionally further having 1 or 2 substituents; Ra is a substituted carbamoyl group; and Rb is an optionally substituted acylamino group, or a salt thereof or a prodrug thereof, which is useful as an agent for the prophylaxis or treatment of GSK-3β related pathology or disease, and a GSK-3β inhibitor including same.
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Page/Page column 30
(2009/07/03)
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- PYRAZOLE COMPOUND
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The present invention provides a pyrazole compound represented by the formula (I): wherein ring A0 is a pyrazole ring optionally further having 1 or 2 substituents; Ra is a substituted carbamoyl group; and Rb is an optionally substituted acylamino group, or a salt thereof or a prodrug thereof, which is useful as an agent for the prophylaxis or treatment of GSK-3β related pathology or disease, and a GSK-3β inhibitor including same.
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Page/Page column 43
(2010/11/28)
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- Nitrodeiodination of 4-iodo-1-methylpyrazoles
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4-Iodo-1-methylpyrazoles react with a nitrating mixture at 55°C to give the corresponding 4-nitro-1-methylpyrazoles. The qualitative dependence of the nitrodeiodination rate on the structure of the heterocycles and the reaction conditions was considered.
- Tret'yakov,Vasilevsky
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p. 2581 - 2584
(2007/10/03)
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- SYNTHESIS OF 3-AMINO-4-NITROPYRAZOLES
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3-Bromo-1,5-dimethyl-4-nitropyrazole does not react upon heating with aqueous ammonia, while 1,5-dimethyl-3,4-dinitropyrazole under the same conditions yields 3-amino-1,5-dimethyl-4-nitropyrazole, which is formed from 3-bromo-1,5-dimethyl-4-nitropyrazole in the presence of a copper catalyst.The amination of 1-methyl-3,4-dinitropyrazole-5-carboxylic acid is accompanied by decarboxylation, which is characteristic for 4-substituted 1-methylpyrazole-5-carboxylic acids upon heating in aqueous ammonia or water.
- Perevalov, V. P.,Andreeva, M. A.,Baryshnenkova, L. I.,Manaev, Yu. A.,Yamburg, G. S.,et al.
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p. 1326 - 1330
(2007/10/02)
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