- HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR AND USE THEREOF
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The present invention relates to a histone acetyltransferase (HAT) inhibitor. Provided are a compound represented by general formula I, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof in the treatment of various HAT-related diseases or conditions.
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- Preparation method of 2-methoxy-6, 7-dihydro-5H-cyclopenta [b] pyridine-5-one
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The invention relates to a preparation method of 2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one. According to the preparation method, ethyl acetoacetate is used as a starting raw material, and anovel target product 2-methoxy-6, 7-dihydro-5H-cyclopenta[b]pyridine-5-one is prepared through nine steps of reactions including dehydration, addition, cyclization, chlorination, bromination, substitution, cyclization again, decarboxylation and etherification. The preparation method of the novel target product is simple and efficient. The purity of the novel target product prepared by the methoddisclosed by the invention reaches over 99.0%.
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Paragraph 0012; 0040-0041; 0055-0058; 0080; 0094-0097; 0119
(2020/08/22)
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- Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)
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The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
- Come, Jon H.,Collier, Philip N.,Henderson, James A.,Pierce, Albert C.,Davies, Robert J.,Le Tiran, Arnaud,O'Dowd, Hardwin,Bandarage, Upul K.,Cao, Jingrong,Deininger, David,Grey, Ron,Krueger, Elaine B.,Lowe, Derek B.,Liang, Jianglin,Liao, Yusheng,Messersmith, David,Nanthakumar, Suganthi,Sizensky, Emmanuelle,Wang, Jian,Xu, Jinwang,Chin, Elaine Y.,Damagnez, Veronique,Doran, John D.,Dworakowski, Wojciech,Griffith, James P.,Jacobs, Marc D.,Khare-Pandit, Suvarna,Mahajan, Sudipta,Moody, Cameron S.,Aronov, Alex M.
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p. 5245 - 5256
(2018/06/08)
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- MODULATORS OF ESTROGEN RECEPTOR PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a cereblon, Von Hippel-Lindau ligase-binding moiety, Inhibitors of Apotosis Proteins, or mouse double-minute homolog 2 ligand, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00477
(2018/08/20)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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- Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that Act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists
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The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl} propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to β-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy} -2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
- Negoro, Nobuyuki,Sasaki, Shinobu,Ito, Masahiro,Kitamura, Shuji,Tsujihata, Yoshiyuki,Ito, Ryo,Suzuki, Masami,Takeuchi, Koji,Suzuki, Nobuhiro,Miyazaki, Junichi,Santou, Takashi,Odani, Tomoyuki,Kanzaki, Naoyuki,Funami, Miyuki,Tanaka, Toshimasa,Yasuma, Tsuneo,Momose, Yu
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p. 1538 - 1552
(2012/04/10)
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- ISOINDOLINONE INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE
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The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Page/Page column 62; 64
(2011/08/04)
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- Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): Structure-activity relationships leading to the identification of 6-((5 S,9 R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7- triazaspiro[4.4]nonan-7-yl)nico
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Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellu
- Watterson, Scott H.,Xiao, Zili,Dodd, Dharmpal S.,Tortolani, David R.,Vaccaro, Wayne,Potin, Dominique,Launay, Michele,Stetsko, Dawn K.,Skala, Stacey,Davis, Patric M.,Lee, Deborah,Yang, Xiaoxia,McIntyre, Kim W.,Balimane, Praveen,Patel, Karishma,Yang, Zheng,Marathe, Punit,Kadiyala, Pathanjali,Tebben, Andrew J.,Sheriff, Steven,Chang, Chiehying Y.,Ziemba, Theresa,Zhang, Huiping,Chen, Bang-Chi,Delmonte, Albert J.,Aranibar, Nelly,McKinnon, Murray,Barrish, Joel C.,Suchard, Suzanne J.,Murali Dhar
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experimental part
p. 3814 - 3830
(2010/07/05)
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- CHEMICAL COMPOUNDS
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The present invention relates to compounds that are a non-nucleoside reverse transcriptase inhibitors, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compounds in the treatment of human immunodeficiency virus infection.
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Page/Page column 76
(2009/01/23)
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- (IMIDAZOLO-5-YL)-2-ANILO-PYRIMIDINES AS AGENTS FOR THE INHIBITION OF CELL PROLIFERATION
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Compounds of the formula (I): wherein variable groups are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti cell proliferation) effect in a warm blooded animal, such as man.
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Page/Page column 3
(2008/06/13)
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