- Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists
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Dopamine (D2) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D 2 partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D2 partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.
- Urbanek, Rebecca A.,Xiong, Hui,Wu, Ye,Blackwell, William,Steelman, Gary,Rosamond, Jim,Wesolowski, Steven S.,Campbell, James B.,Zhang, Minli,Brockel, Becky,Widzowski, Daniel V.
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- Fragment-based discovery of type i inhibitors of maternal embryonic leucine zipper kinase
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Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.
- Johnson, Christopher N.,Berdini, Valerio,Beke, Lijs,Bonnet, Pascal,Brehmer, Dirk,Coyle, Joseph E.,Day, Phillip J.,Frederickson, Martyn,Freyne, Eddy J. E.,Gilissen, Ron A. H. J.,Hamlett, Christopher C. F.,Howard, Steven,Meerpoel, Lieven,McMenamin, Rachel,Patel, Sahil,Rees, David C.,Sharff, Andrew,Sommen, Franois,Wu, Tongfei,Linders, Joannes T. M.
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- CYANOINDOLINE DERIVATIVES AS NIK INHIBITORS
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Fused aromatic bicyclic substituted 5-(2-amino-4-pyrimidinyl)- cyanoindoline derivatives (I) useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-KB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
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Page/Page column 284
(2018/02/03)
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- BENZOLACTAM COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The invention provides a compound of formula (0): or a pharmaceutically acceptable salt, N-oxide or tautomer thereof. The compounds are inhibitors of ERK 1/2 kinases and will be useful in the treatment of ERKl/2-mediated conditions. The compounds are therefore useful in therapy, in particular in the treatment of cancer.
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Page/Page column 278; 279
(2017/08/01)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of one or more protein kinases. Such compounds have general formula I or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, W, Ry, R3 and R4 are as defined herein.
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- Efficient and scalable synthesis of thiazole fused benzazepine as a D2 partial agonist
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The development of an efficient and scalable synthetic route to prepare the selective D2 partial agonist (1) is described here. Regioselective nitration of tetrahydrobenzazepine 2, followed by reductive amination, hydrogenation, and oxidative cyclization
- Xiong, Hui,Wu, Ye,Lehr, Scott G.,Blackwell, William,Steelman, Gary,Hulsizer, Jim,Urbanek, Rebecca A.
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p. 5833 - 5836,4
(2020/07/31)
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- 7-Sulfonamido-3-benzazepines as potent and selective 5-HT2C receptor agonists: Hit-to-lead optimization
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New 7-sulfonamido-3-benzazepines 3 are disclosed as 5-HT2C receptor agonists. Appropriate substitution of the amino group (R1R2N-) gave compounds that were potent 5-HT2C agonists with minimal activation of the 5-HT2A and 5-HT2B receptors. Furthermore, representative examples had excellent in vitro ADME properties and good selectivity over ion channel activity.
- Fish, Paul V.,Brown, Alan D.,Evrard, Edel,Roberts, Lee R.
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scheme or table
p. 1871 - 1875
(2009/12/03)
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- Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists
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Starting from a benzazepine sulfonamide 5-HT6 receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivati
- Trani, Giancarlo,Baddeley, Stuart M.,Briggs, Michael A.,Chuang, Tsu T.,Deeks, Nigel J.,Johnson, Christopher N.,Khazragi, Abir A.,Mead, Tania L.,Medhurst, Andrew D.,Milner, Peter H.,Quinn, Leann P.,Ray, Alison M.,Rivers, Dean A.,Stean, Tania O.,Stemp, Geoffrey,Trail, Brenda K.,Witty, David R.
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scheme or table
p. 5698 - 5700
(2009/06/18)
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- COMPOUNDS HAVING AFFINITY FOR THE DOPAMINE D3 RECEPTOR AND USES THEREOF IN MEDICINE
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Compounds of formula (I) or a salt thereof are disclosed, wherein A, m R1, R2, R3, q, W1, W2, R4 and R5 are as defined in the description. Processes for preparation and uses of the compounds in medicine, for example for the treatment of schizophrenia or drug dependency, are also disclosed.
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Page/Page column 25-26
(2010/02/15)
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- COMPOUNDS HAVING AFFINITY FOR DOPAMINE D3 RECEPTOR AND USES THEREOF
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Compounds of formula (I) and salts thereof are disclosed: wherein A, R1, m, R2, n, R3, R4, q, W1, W2, R5 and R6 are as defined in the description. Methods of preparing the compounds and uses thereof in medicine, for example in the treatment of schizophrenia or drug dependency, are also disclosed.
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Page/Page column 37
(2010/02/15)
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- SULFONAMIDE DERIVATIVES AS ANTIPSYCHOTIC AGENTS
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The invention provides compounds of formula (I) wherein A and B represent the groups -(CH2)m- and -(CH2)n- respectively; R1 represents C1-6alkyl; R2 represents hydrogen, halogen,
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- DOPAMINE RECEPTOR MODULATORS AS ANTIPSYCHOTIC AGENTS
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The invention provides compounds of formula (I):wherein A and B represent the groups -(CH2)m- and -(CH2)n-respectively; R1 represents hydrogen or C1-6alkyl; R2 represents hydroge
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Page/Page column 18
(2010/02/07)
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- Cyclic derivatives pharmaceutical compositions containing these compounds and processes for preparing them
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The invention relates to cyclic derivatives of general formula STR1 wherein Ra, Rb, X and Y are as defined in claim 1, the tautomers, the stereoisomers including the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable pharmacological properties, preferably aggregation-inhibiting effects, pharmaceutical compositions containing the compounds and processes for preparing them.
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