- Spiro compounds, preparation method thereof, intermediate, pharmaceutical composition and application
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The invention discloses a spiro compound as shown in a formula I, a pharmaceutically acceptable salt, a hydrate, a solvate, an optical isomer or a prodrug of the spiro compound, as well as a preparation method, an intermediate, a pharmaceutical composition and an application of the spiro compound. The spiro compound disclosed by the invention has the activity of serving as protein kinase inhibitors and tyrosine kinase inhibitors such as c-Met, and the spiro compound can be used for treating diseases caused by the abnormal activity of kinases, such as cancer, or used for preparing medicaments for treating the diseases.
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- Identification of novel p38α MAP kinase inhibitors using fragment-based lead generation
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We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyl-oxypyridine 1 (IC50 1.3 mM) and 3-(2-(4-pyridyl) ethyl)indole 2 (IC50 35 μM) identified using X-ray crystallographic screening of p38α MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
- Gill, Adrian L.,Frederickson, Martyn,Cleasby, Anne,Woodhead, Steven J.,Carr, Maria G.,Woodhead, Andrew J.,Walker, Margaret T.,Congreve, Miles S.,Devine, Lindsay A.,Tisi, Dominic,O'Reilly, Marc,Seavers, Lisa C. A.,Davis, Deborah J.,Curry, Jayne,Anthony, Eachel,Padova, Alessandro,Murray, Christopher W.,Carr, Robin A. E.,Jhoti, Harren
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p. 414 - 426
(2007/10/03)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
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- 3-`(HETERO) ARYLMETHOXY ! PYRIDINES AND THEIR ANALOGUES AS P38 MAP KINASE INHIBITORS
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Compounds of the formula (I), wherein: -X=Y- is selected from -CR2=CR3- and -CR2=N-; R1 is selected from H, halo, NRR', NHC(=O)R, NHC(=O)NRR', NH2SO2R, and C(=O)NRR'; R2 and R3 (where present) are independently selected from H, optionally substituted C1-7 alkyl, optionally substituted C5-20 aryl, optionally substituted C3-20 heterocyclyl, halo, amino, amido, hydroxy, ether, thio, thioether, acylamido, ureido and sulfonamino; R4 is an optionally substituted C5-20 aryl or C5-20 heteroaryl group; and R5 is selected from R5’, halo, NHR5’, C(=O)NHR5’, OR5’, SR5’, NHC(=O)R5’, NHC(=O)NHR5’, NHS(=O)R5’, wherein R5’ is H or C1-3 alkyl (optionally substituted by halo, NH2, OH, SH) are disclosed for use in therapy and for treating diseases ameliorated by inhibiting p38 MAP kinase.
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Page/Page column 66
(2010/11/30)
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- A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework
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A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-α]pyridine derivative 2. The unique screening lead (2) was discovered b
- Abe, Yoshito,Kayakiri, Hiroshi,Satoh, Shigeki,Inoue, Takayuki,Sawada, Yuki,Imai, Keisuke,Inamura, Noriaki,Asano, Masayuki,Hatori, Chie,Katayama, Akira,Oku, Teruo,Tanaka, Hirokazu
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p. 564 - 578
(2007/10/03)
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- [(alkoxy)pyridinyl]amine compounds which are useful in the treatment of gastrointestinal disorders
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The present invention relates to N-pyridylamidine and N-pyridylguanidine derivatives of general formula (I) in which: Ar1 is an optionally substituted phenyl ring; Ar2 is an optionally substituted phenyl ring; R1 is hydrogen or C1-4 alkyl; R2 is hydrogen or C1-4 alkyl; R3 is hydrogen or C1-4 alkyl; R4 is hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy; X is CH2 or NR5, and R5 is hydrogen or C1-4 alkyl, and the salts thereof, and their use in therapy as gastric acid secretion inhibitors.
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- Certain imidazo[1,2-a]pyridines useful in the treatment of ulcers
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Certain imidazo[1,2-a]heterocyclic compounds useful in the treatment of ulcers are provided.
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