- N-methyltriazine synthesis method
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The invention discloses an N-methyltriazine synthesis method, which comprises the following steps of S1, dissolving cyanogen chloride and acetonitrile in a solvent, adding a catalyst and hydrogen chloride, and carrying out a reaction to obtain 2-methyl-4, 6-dichloro-1, 3, 5-s-triazine, S2, enabling 2-methyl-4, 6-dichloro-1, 3, 5-s-triazine to react with sodium methoxide to obtain 2-methyl-4-methoxy-6-chloro-1, 3, 5-s-triazine, and S3, carrying out condensation reaction on the 2-methyl-4-methoxy-6-chloro-1, 3, 5-s-triazine and methylamine to obtain the N-methyl triazine. The invention provides a novel reaction route for synthesizing N-methyltriazine, the cost of used raw materials is low, the yield of synthesized N-methyltriazine is high and reaches 96% or above, potential safety hazards caused by chlorine and Grignard reagents used in a traditional synthesis method are avoided, and industrial production is facilitated.
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Paragraph 0021-0024; 0029-0032; 0037-0040; 0045-0048
(2021/04/26)
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- Synthesis method of dihalogenated s-triazine
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The invention discloses a synthesis method of dihalogenated s-triazine. The method comprises the following steps: dissolving a substituted nitrile compound and a halogenated nitrile compound in a certain solvent, adding a certain catalyst, and introducing halogenated hydrogen at a certain temperature for a certain period of time, and reacting to obtain the dihalogenated s-triazine. The invention provides a new reaction route for synthesizing the dihalogenated s-triazine, the dihalogenated s-triazine is prepared by taking the substituted nitrile compound and the halogenated nitrile compound as raw materials and adopting a one-step reaction, the reaction steps and process are saved, the process is simple and convenient, the cost is low, the product yield is high and reaches 99 percent or above, and moreover, a dangerous process of Grignard reaction is avoided in the synthesis process, the production risk is reduced, and meanwhile, the problem of environmental pollution is avoided.
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Paragraph 0032-0035
(2021/04/14)
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- SARs of a novel series of s-triazine compounds targeting vimentin to induce methuotic phenotype
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Herein, we describe the design, synthesis and structure?activity relationships of a series of novel s-triazine compounds can induce methuotic phenotype in various types of cancer cells. (E)-1-(4-Chlorophenyl)-3-(4-((4-morpholino-6-styryl-1,3,5-triazine-2-yl)amino)phenyl)urea, compound V6, exhibited a striking methuotic phenotype with a minimal effective concentration of less than 10 nM in U87 glioblastoma cells. Based on structure?activity relationship studies, we designed and synthesized an active probe P1 that retained the full potential of V6 in inducing the methuotic phenotype in U87 glioblastoma cells. Using this probe following affinity-based proteomic profiling strategy, we identified vimentin as the specific target protein of compound V6. Molecular docking revealed that V6 can form hydrogen bonds with vimentin at 273R and 276Y in its rod domain.
- Zhang, Lei,Qu, Zhipeng,Wu, Jianping,Yao, Shining,Zhang, Qingqing,Zhang, Tao,Mo, Lian,Yao, Qizheng,Xu, Ying,Chen, Ruihuan
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- Trizaine-based dehydrative condensation reagents bearing carbon-substituents
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Herein, we report on the synthesis of alkyl-, aryl-, and alkynyl-substituted chlorotriazines and their ammonium salts, and demonstrate their utility in dehydrative condensation reactions. Although the electrophilicity of these reagents is mainly dependent on the hybridization of the carbon-substituents, it was found that bulky 2,6-dimethylphenyl group-substituted reagents resulted in the highest product yields because of a slight increase in reagent electrophilicity and/or steric hindrance favorable for desired dehydrative condensation reactions.
- Kitamura, Masanori,Komine, Sayaka,Kunishima, Munetaka,Yamada, Kohei
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- NOVEL 2,4,6-TRISUBSTITUTED S-TRIAZINE COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF
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The present invention provides a 2,4,6-trisubstituted s-triazine compound represented by general formula (I) or pharmaceutically acceptable salts, prodrugs or solvates thereof, a preparation method therefor, and use of these compounds in preparing drugs for preventing or treating diseases associated with protein kinase and vimentin dysregulation, and cell vacuolization, and in particular, drugs for treating or preventing cancer growth and metastasis, tissue fibrosis and atherosclerosis.
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Paragraph 0069
(2019/04/05)
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- NITROGEN HEXACYCLE COMPOUNDS AS INHIBITORS OF p97 COMPLEX
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Nitrogen hexacycle compounds having an arylalkyl amine substituent at the P4 position and a substituted 5:6 bicyclic group at the P2 position of the nitrogen hexacycle as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the nitrogen hexacycle, the aryl alkyl group and the 5:6 bicyclic group are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.
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Paragraph 2103-2104
(2016/12/22)
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- Synthesis and PGE2 production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells
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We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10 μM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52 μM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R1 = 4-Bn-Ph, R2 = Cl, R3 = Ph, R5 = CO2Me) was highly active in cells while maintaining little COX-2 inhibition (~0% at 10 μM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure-activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor.
- Kang, Seoung Mook,Lee, Jinsung,Jin, Jae Ho,Kim, Minju,Lee, Sunhoe,Lee, Hwi Ho,Shin, Ji-Sun,Lee, Kyung-Tae,Lee, Jae Yeol
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p. 5418 - 5422
(2015/01/08)
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- Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase
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1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N- {[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.
- Thalji, Reema K.,McAtee, Jeff J.,Belyanskaya, Svetlana,Brandt, Martin,Brown, Gregory D.,Costell, Melissa H.,Ding, Yun,Dodson, Jason W.,Eisennagel, Steve H.,Fries, Rusty E.,Gross, Jeffrey W.,Harpel, Mark R.,Holt, Dennis A.,Israel, David I.,Jolivette, Larry J.,Krosky, Daniel,Li, Hu,Lu, Quinn,Mandichak, Tracy,Roethke, Theresa,Schnackenberg, Christine G.,Schwartz, Benjamin,Shewchuk, Lisa M.,Xie, Wensheng,Behm, David J.,Douglas, Stephen A.,Shaw, Ami L.,Marino Jr., Joseph P.
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supporting information
p. 3584 - 3588
(2013/07/19)
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- Structure-based design of a novel series of potent, selective inhibitors of the class i phosphatidylinositol 3-kinases
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A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
- Smith, Adrian L.,D'Angelo, Noel D.,Bo, Yunxin Y.,Booker, Shon K.,Cee, Victor J.,Herberich, Brad,Hong, Fang-Tsao,Jackson, Claire L. M.,Lanman, Brian A.,Liu, Longbin,Nishimura, Nobuko,Pettus, Liping H.,Reed, Anthony B.,Tadesse, Seifu,Tamayo, Nuria A.,Wurz, Ryan P.,Yang, Kevin,Andrews, Kristin L.,Whittington, Douglas A.,McCarter, John D.,Miguel, Tisha San,Zalameda, Leeanne,Jiang, Jian,Subramanian, Raju,Mullady, Erin L.,Caenepeel, Sean,Freeman, Daniel J.,Wang, Ling,Zhang, Nancy,Wu, Tian,Hughes, Paul E.,Norman, Mark H.
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experimental part
p. 5188 - 5219
(2012/08/28)
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- ARYL CARBOXAMIDE DERIVATIVES AS SODIUM CHANNEL INHIBITORS FOR TREATMENT OF PAIN
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The present invention provides compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav 1.7, and are therefore useful for the treatment of diseases treatable by inhibition of these channels, in particular, chronic pain disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 108
(2011/09/19)
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- Discovery of triazine-benzimidazoles as selective inhibitors of mTOR
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mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3Kα. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC50 of 0.41 μM. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.
- Peterson, Emily A.,Andrews, Paul S.,Be, Xuhai,Boezio, Alessandro A.,Bush, Tammy L.,Cheng, Alan C.,Coats, James R.,Colletti, Adria E.,Copeland, Katrina W.,Dupont, Michelle,Graceffa, Russell,Grubinska, Barbara,Harmange, Jean-Christophe,Kim, Joseph L.,Mullady, Erin L.,Olivieri, Philip,Schenkel, Laurie B.,Stanton, Mary K.,Teffera, Yohannes,Whittington, Douglas A.,Cai, Ti,La, Daniel S.
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scheme or table
p. 2064 - 2070
(2011/04/24)
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- INDOLE/BENZIMIDAZOLE COMPOUNDS AS mTOR KINASE INHIBITORS
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The present invention provides compounds that are kinase inhibitors, specifically PIK kinase inhibitors, more specifically, mTOR inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of kinases, specifically PIK kinase inhibitors, more specifically, mTOR such as cancer. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds
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Page/Page column 48
(2010/09/17)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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Compounds of the formula (I) and formula (II) and pharmaceutically acceptable salts thereof.
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Page/Page column 114
(2010/12/29)
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- STYRYL-TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The invention provides Styryl-Triazine derivatives, and further provides methods of using these compounds to modulate protein kinases and to treat protein kinase mediated diseases
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Page/Page column 80
(2010/12/29)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention comprises inter alia compounds as shown in formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 84
(2010/12/29)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention comprises inter alia triazine compounds as shown in formula (I) and pharmaceutically acceptable salts thereof.
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Page/Page column 76; 77
(2010/12/29)
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- Anarchy in the solid state: structural dependence on glass-forming ability in triazine-based molecular glasses
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We have recently shown that molecular glasses, small molecules capable of readily forming glassy solids as opposed to crystals, can be designed by exploiting molecular association through strong and directional intermolecular interactions, as exemplified by several members of the bis(mexylamino)triazine family. Herein, 43 new bis(mexylamino)triazine derivatives were synthesized, 31 of which have been found to spontaneously form glassy phases and did not crystallize upon heating. Crown Copyright
- Wuest, James D.,Lebel, Olivier
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experimental part
p. 7393 - 7402
(2009/12/06)
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- NOVEL sEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I: wherein R1, R2, R5a, R6a, A, B, Y, I, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 23-24
(2009/05/28)
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- NOVEL SEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I: (I) wherein R1, R2, R3, R5a, R6a A, B, Y, x, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 23; 55
(2009/05/28)
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- NOVEL SEH INHIBITORS AND THEIR USE
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The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme. Specifically, the invention is directed to compounds according to Formula I: wherein R1, R2, R4, R5, R6, A, B, Y, Z, n, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 32
(2009/05/28)
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- TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
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The invention provides for Triazine derivatives and their use to modulate protein kinase activity in a variety of conditions and diseases.
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Page/Page column 54
(2008/12/06)
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- COMPOUNDS AND METHODS FOR THE TREATMENT OF VIRUSES AND CANCER
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The present invention relates to compounds according to the formula I: Where Ra is H or an optionally OH-substituted C1-C3 alkyl; R1 is OR1, an optionally substituted C4-12 carbocyclic group which may be saturated or unsaturated (including aromatic) or an optionally substituted heterocyclic group; R1 is an optionally substituted C1-C14 hydrocarbyl group or an optionally substituted heterocyclic group;; R2 , R3 and R4 are each independently H, an optionally substituted C1-C4 alkyl group (preferably CH3, CH2CH3 or CF3), halogen (preferably F, Cl, Br), OR, CN, NO2, a C1-C6 thioether, a C1-C6 thioester group, an optionally substituted CO2R group, an optionally substituted COR group or an optionally substituted OCOR group (preferably R4 is H); R is H or an optionally substituted C1-C6 alkyl group; RHET is an optionally substituted heterocyclic group; and pharmaceutically acceptable salts, solvates or polymorphs thereof.
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Page/Page column 31-32
(2010/11/26)
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- Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase are being pursued through synthesis and assaying for anti-viral activity. Following computational analyses, the focus has been on the motif Het-NH-Ph-U, where Het is an aromatic heterocycle and U is an unsaturated, hydrophobic group. Previous investigations with Het = 2-thiazoyl and 2-pyrimidinyl are extended here to triazinyl derivatives. The result is several NNRTIs in the 2-20 nM range with negligible cytotoxicity and auspicious predicted pharmacological properties.
- Thakur, Vinay V.,Kim, Joseph T.,Hamilton, Andrew D.,Bailey, Christopher M.,Domaoal, Robert A.,Wang, Ligong,Anderson, Karen S.,Jorgensen, William L.
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p. 5664 - 5667
(2007/10/03)
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- INDAZOLINONE COMPOSITIONS USEFUL AS KINASE INHIBITORS
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The present invention provides compounds of formula (I): These compounds, and pharmaceutically acceptable compositions thereof, are useful generally as kinase inhibitors, particularly as inhibitors of PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, and Aurora-2. Accordingly, compounds and compositions of the invention are useful for treating or lessening the severity of a variety of disorders, including, but not limited to, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases.
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- 1N-ALKYL-N-ARYLPYRIMIDINAMINES AND DERIVATIVES THEREOF
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The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer'disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R 1, R 3, R 4, R 5, Z, Y, V, X, X', J, K, L, and M are as defined herein.
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- 1N-alkyl-N-arylpyrimidinamines and derivatives thereof
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The present invention provides novel compounds, compounds and pharmaceutical compositions thereof, and methods of using same in the treatment of affective disorders, anxiety, depression, post-traumatic stress disorders, eating disorders, supranuclear palsy, irritable bowel syndrome, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa, drug and alcohol withdrawal symptoms, drug addiction, inflammatory disorders, or fertility problems. The novel compounds provided by this invention are those of formula: wherein R1, R3, R4, R5, Z, Y, V, X, X', J, K, L, and M are as defined herein.
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- Aryl- and arylamino- substituted heterocycles as corticotropin releasing hormone antagonists
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Corticotropin releasing factor (CRF) antagonists of formula I: and their use in treating psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
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- Non-peptide corticotropin-releasing hormone antagonists: Syntheses and structure activity relationships of 2-anilinopyrimidines and -triazines
-
Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist α-helical CRH(9- 41) (K(i) = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH- stimulated adenylate cyclase activity in the same tissue, but it was less potent than α-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH(1)K(1) = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.
- Arvanitis, Argyrios G.,Gilligan, Paul J.,Chorvat, Robert J.,Cheeseman, Robert S.,Christos, Thomas E.,Bakthavatchalam, Rajagopal,Beck, James P.,Cocuzza, Anthony J.,Hobbs, Frank W.,Wilde, Richard G.,Arnold, Charles,Chidester, Dennis,Curry, Matthew,He, Liqi,Hollis, Andrea,Klaczkiewicz, John,Krenitsky, Paul J.,Rescinito, Joseph P.,Scholfield, Everett,Culp, Steven,De Souza, Errol B.,Fitzgerald, Lawrence,Grigoriadis, Dimitri,Tam, S. William,Wong, Y. Nancy,Huang, Shiew-Mei,Shen, Helen L.
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p. 805 - 818
(2007/10/03)
-
- Preparation of methyl-1,3-5-triazines
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A method for making methyl-1,3,5-triazines including the 2,4-dichloro-6-methyl- and the 2-methyl-4-methylamino-6-methoxy-1,3,5-triazines, comprising reacting sodium dicyanamide with a cyclizing agent in the presence of HCl to make the 2,4-dichloro-6-methyl-triazine and reacting said triazine, additionally, with sodium methoxide and monomethylamine to make the 2-methyl-4-methylamino-6-methoxytriazine.
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