- Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound
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Disclosed are a nitrogen heterocyclic compound represented by a formula (I), a pharmaceutical composition comprising the same, and a preparation method and use of the nitrogen heterocyclic compound, and in particular, relates to the use of the nitrogen heterocyclic compound for prevention or treatment of diseases or conditions associated with RET activity.
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Paragraph 0493; 0494; 0498-0500
(2020/08/18)
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- JANUS KINASE 1 SELECTIVE INHIBITOR AND PHARMACEUTICAL USE THEREOF
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Janus kinase 1 selective inhibitors and pharmaceutical use thereof are provided.
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Paragraph 0255-0262
(2018/06/07)
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- Design, synthesis and evaluation of (R)-3-(7-(methyl?7H-pyrrolo?2, 3-d]pyrimidin-4-yl)amino)-5-azaspiro?2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor
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Based on (R)-N-methyl-N-(5-azaspiro?2.4]heptan-7-yl)-7H-pyrrolo?2, 3-d]pyrimidin-4-amine as a core scaffold, we identified (R)-3-(7-(methyl?7H-pyrrolo?2, 3-d]pyrimidin-4-yl)amino)-5-azaspiro?2.4]heptan-5- yl)-3-oxopropanenitrile [(R)-6c] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinib's 7-deazapurine and 5-azaspiro?2.4]heptan-7-amine. Compound (R)-6c exhibited an IC50 value of 8.5 nM against JAK1 with a selectivity index of 48 over JAK2. To optimize (R)-6c as a lead compound, we performed in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Mouse and rat in vivo studies verified that (R)-6c exhibited desired efficacies in CIA and AIA models.
- Chough, Chieyeon,Lee, Sunmin,Joung, Misuk,Lee, Jaemin,Kim, Jong Hoon,Kim, B. Moon
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supporting information
p. 477 - 489
(2018/03/28)
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- Benzamide Hedgehog inhibitor as well as preparation method and application thereof
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The invention discloses a benzamide Hedgehog inhibitor as well as a preparation method and application thereof. The inhibitor has the structure show as a general formula (I) (shown in the specification). Compared with the prior art, a novel benzamide compound provided by the invention is capable of targeting Smoothened proteins in a Hedgehog signal channel, the drug resistance caused by mutation of a Smoothened acceptor can be effectively avoided, so that the Hedgehog signal channel can be effectively inhibited, and Hedgehog signal channel relevant tumors, such as basal cell carcinoma (BCCs), medulloblastoma, breast carcinoma, colon cancer or lung cancer, can be effectively treated.
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Page/Page column 8; 9
(2017/10/07)
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- An efficient palladium-catalyzed synthesis of 1-heteroaryl-4-aminopiperidine derivatives from heteroaryl chlorides
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An efficient protocol for the synthesis of 1-heteroaryl-4-(N-methyl)aminopiperidines starting from heteroaryl chloride derivatives is described. A broad range of 1-heteroaryl-4-(N-Boc-N-methyl)aminopiperidine derivatives were obtained in good to excellent
- Zhang, Kena,Li, Hui,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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supporting information
p. 1976 - 1979
(2017/04/27)
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- A novel and efficient route for synthesis of Taladegib
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Taladegib (LY-2940680), a small molecule Hedgehog signalling pathway inhibitor, was obtained from N-benzyl-4-piperidone via Borch reductive amination, acylation with 4-fluoro-2-(trifluoromethyl)benzoyl chloride, debenzylation, substitution with 1,4-dichlorophthalazine and Suzuki cross-coupling reaction with 1-methyl-1H-pyrazole-5-boronic acid. The advantages of this synthesis route were the elimination of Boc protection and deprotection and the inexpensive starting materials. Furthermore, the debenzylation reaction was achieved with simplified operational procedure using ammonium formate as hydrogen source that provided high reaction yield. This synthetic procedure was suitable for large-scale production of the compound for biological evaluation and further study.
- Guo, Mingliang,Hong, Kwon Ho,Lv, Yongfeng,Ding, Yu,Li, Congcong,Xu, Hua,Qi, Wenxiu,Chen, Junqing,Ji, Min,Cai, Jin
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p. 112 - 115
(2017/03/14)
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- Synthetic method of Taladegib
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The invention discloses a synthetic method of Taladegib. The synthetic method is characterized by comprising the following steps that reductive amination is carried out on N-benzyl-4-piperidone to obtain a compound in formula VI; in the presence of an organic base, an acylation reaction is carried out on the compound in the formula VI and an acylation reagent to obtain a compound in the formula VIII; the acylation reagent is 4-fluoro-2-(trifluoromethyl)benzoyl chloride; in the presence of a hydrogen source and a palladium catalyst, debenzylation is carried out on the compound in formula VIII to obtain a compound in the formula IX; in the presence of an inorganic base, the compound in the formula IX is reacted with 1,4-dichloro phthalazine to obtain a compound in the formula X; in the presence of the inorganic base and the palladium catalyst, an SUZUKI coupling reaction is carried out on the compound in the formula X and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain Taladegib. According to the invention, the process route is improved, cheap N-benzyl-4-piperidone is taken as a starting material, the processes of Boc protection and deprotection are removed to reduce the synthesis steps and reduce the production cost.
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Paragraph 0036; 0038; 0039
(2017/08/25)
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- QUINAZOLINE COMPOUNDS AND THEIR USE IN THERAPY
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This invention relates to quinazoline compounds of Formula (I) which are inhibitors of the histone lysine methyltransferase (HKMTase) EZH2, and to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of EZH2 provides a therapeutic or prophylactic effect.
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Page/Page column 65
(2013/10/08)
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- Substituted Benzamide Compounds
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Substituted benzamide compounds corresponding to formula (I) in which R5, R6, R7, R8, a, b, c, d, t, D and X have defined meanings, a process for their preparation, pharmaceutical compositions comprising such compounds, and a method of using such compounds to treat pain and other conditions mediated at least in part via the bradykinin 1 receptor.
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Page/Page column 144
(2012/04/04)
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- NEW COMPOUNDS, PHARMACEUTICAL COMPOSITION AND METHODS RELATING THERETO
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New compounds are disclosed which have utility in the treatment of a variety of metabolic related conditions in a patient. The compounds of this invention have the structure (I): wherein X1, X2, X3, X4, Y1
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Page/Page column 39
(2011/01/12)
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- The design and discovery of novel amide CCR5 antagonists
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The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
- Pryde, David C.,Corless, Martin,Fenwick, David R.,Mason, Helen J.,Stammen, Blanda C.,Stephenson, Peter T.,Ellis, David,Bachelor, David,Gordon, David,Barber, Christopher G.,Wood, Anthony,Middleton, Donald S.,Blakemore, David C.,Parsons, Gemma C.,Eastwood, Rachel,Platts, Michelle Y.,Statham, Keith,Paradowski, Kerry A.,Burt, Catherine,Klute, Wolfgang
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supporting information; scheme or table
p. 1084 - 1088
(2009/08/07)
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- PIPERIDINE DERIVATIVES HAVING CCR3 ANTAGONISM
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The invention provides low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists. The invention also provides compounds represented by formula (I) below, pharmaceutically acceptable acid adducts thereof, or pharmaceutically acceptable C1-C6 alkyl adducts thereof, as well as pharmaceutical compositions comprising them as effective ingredients, which are useful for treatment or prevention of diseases associated with CCR3, such as asthma and allergic rhinitis.
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- Neurokinin antagonists
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The invention relates to new compounds of formula I 1or the pharmaceutically acceptable salts thereof, wherein R1 denotes 3-hydroxypropyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl, and R2, R3, R4 and Ar have the meanings given in the specification, as well as the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin) antagonists.
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- Heterocyclic compounds for the treatment of CNS and cardiovascular disorders
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Novel aromatic bicyclic amines of formula (I) STR1 are useful in treating central nervous system disorders and cardiac arrhythmias and cardiac fibrillation.
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- 3-[3-(piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor agonists
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Several 5-HT(ID/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D)receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to the identification of 80 (L-772,405), a high- affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5- HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.
- Russell, Michael G. N.,Matassa, Victor G.,Pengilley, Roy R.,Van Niel, Monique B.,Sohal, Bindi,Watt, Alan P.,Hitzel, Laure,Beer, Margaret S.,Stanton, Josephine A.,Broughton, Howard B.,Castro, José L.
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p. 4981 - 5001
(2007/10/03)
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- Alkyl substituted piperadinyl and piperazinyl anti-AIDS compounds
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Anti-AIDS compounds of formula (I) STR1 wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification and R8 is alkyl of substituted alkyl.
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- Targeting delavirdine/atevirdine resistant HIV-1: Identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors
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A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.
- Romero, Donna L.,Olmsted, Robert A.,Poel, Toni Jo,Morge, Raymond A.,Biles, Carolyn,Keiser, Barbara J.,Kopta, Laurice A.,Friis, Jan M.,Hosley, John D.,Stefanski, Kevin J.,Wishka, Donn G.,Evans, David B.,Morris, Joel,Stehle, Randy G.,Sharma, Satish K.,Yagi, Yoshihiko,Voorman, Richard L.,Adams, Wade J.,Tarpley, W. Gary,Thomas, Richard C.
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p. 3769 - 3789
(2007/10/03)
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- Diarylalkyl-substituted alkylamines and medicaments containing them
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A compound I STR1 in which R1 is cycloalkyl, alkenyl, cycloalkenyl, phenyl, STR2 where J, L, M, and E are methine or nitrogen and J', L', M', and E' are methylene, carbonyl or imino; R2 is phenyl or phenylalkyl; a is various amine ra
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