- Synthesis of 4-alkyl-3,5-dibromo-, 3-bromo-4,5-dialkyl- and 3,4,5-trialkylpyridines via sequential metalation and metal-halogen exchange of 3,5-dibromopyridine
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Lithiation of 3,5-dibromopyridine with LDA and subsequent reaction with electrophiles provided 4-alkyl-3,5-dibromopyridines 2 in high yield. 3-Bromo-4,5-dialkylpyridines 3 were synthesized by metal-halogen exchange of 2 with one equivalent n-BuLi and reaction with a second electrophile. Further metal-halogen exchange of 3 and reaction with a third electrophile provided 3,4,5-trisubstituted pyridines 4.
- Gu,Bayburt
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- ISOQUINOLINES AS INHIBITORS OF HPK1
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Isoquinoline compounds and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibitng HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.
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Paragraph 0778; 0779
(2018/10/21)
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- Discovery of novel 1,2,4-thiadiazole derivatives as potent, orally active agonists of sphingosine 1-phosphate receptor subtype 1 (S1P1)
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A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P1 agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (Fu > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.
- Ren, Feng,Deng, Guanghui,Wang, Hailong,Luan, Linbo,Meng, Qinghua,Xu, Qiongfeng,Xu, Heng,Xu, Xuesong,Zhang, Haibo,Zhao, Baowei,Li, Chengyong,Guo, Taylor B.,Yang, Jiansong,Zhang, Wei,Zhao, Yonggang,Jia, Qiantao,Lu, Hongtao,Xiang, Jia-Ning,Elliott, John D.,Lin, Xichen
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supporting information; experimental part
p. 4286 - 4296
(2012/07/03)
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