- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided are 2-(piperidin-1-yl)pyrimidin-4(3H)-ones or pharmaceutically acceptable salts thereof, each characterized by having a 1,8-diazaspiro[4.5]deca-3-ene, 1-oxa-8-azaspiro[4.5]deca-3-ene, 2,8-diazaspiro[4.5]deca-3-ene, 2-oxa-8-azaspiro[4.5]deca-3-ene, 2,9-diazaspiro[5.5]undeca-3-ene, 1-oxa-9-azaspiro[5.5]undeca-3-ene, 1,9-diazaspiro[5.5]undeca-4-ene, or 3,9-diazaspiro[5.5]undeca-1-ene structure represented by the following general formula (1):
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Paragraph 0237; 0238
(2019/05/16)
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- SUBSTITUTED HETEROCYCLIC DERIVATIVES AS GPR AGONISTS AND USES THEREOF
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The present invention generally relates to substituted heterocyclic derivatives (the compounds of Formula (I)), processes for their preparation, pharmaceutical compositions containing said compounds, their use as G-protein coupled receptor (GPR) agonists, particularly as GPR40 agonists and methods of using these compounds in the treatment of GPR40 mediated diseases or conditions such as Type 2 diabetes, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
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Page/Page column 86; 149; 150
(2015/03/16)
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- Conformationally constrained ortho- Anilino diaryl ureas: Discovery of 1-(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl) -3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist
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Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
- Qiao, Jennifer X.,Wang, Tammy C.,Ruel, Réjean,Thibeault, Carl,L'Heureux, Alexandre,Schumacher, William A.,Spronk, Steven A.,Hiebert, Sheldon,Bouthillier, Gilles,Lloyd, John,Pi, Zulan,Schnur, Dora M.,Abell, Lynn M.,Hua, Ji,Price, Laura A.,Liu, Eddie,Wu, Qimin,Steinbacher, Thomas E.,Bostwick, Jeffrey S.,Chang, Ming,Zheng, Joanna,Gao, Qi,Ma, Baoqing,McDonnell, Patricia A.,Huang, Christine S.,Rehfuss, Robert,Wexler, Ruth R.,Lam, Patrick Y. S.
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supporting information
p. 9275 - 9295
(2014/01/06)
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- COMPOUNDS AND THERAPEUTIC USES THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and complications associated w
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Page/Page column 106-107
(2013/02/28)
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- A facile synthesis of the spiroindoline-based growth hormone secretagogue, MK-677
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A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677 was described. The key step adopted the Fischer indole/reduction strategy. The preparation of the key intermediates N-protected piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-d-serine (2) are also optimized.
- Qi, Xian Liang,Yang, Er Qun,Zhang, Jun Tao,Wang, Tao,Cao, Xiao Ping
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p. 661 - 664
(2012/07/03)
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- NOVEL SPIROPIPERIDINE COMPOUNDS
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A compound of the formula: or a pharmaceutically acceptable salt thereof as well as a pharmaceutical composition, and a method for treating diabetes.
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Page/Page column 11
(2011/06/23)
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- Novel Spiropiperidine Compounds
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A compound of the formula: or a pharmaceutically acceptable salt thereof as well as a pharmaceutical composition, and a method for treating diabetes.
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Page/Page column 8
(2011/05/03)
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- One-pot synthesis of highly substituted indolines
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A general and convenient one-pot synthesis of highly substituted indolines from arylhydrazines and aldehydes is reported. This synthesis allows introduction of substitution at essentially all positions of the indoline nucleus to achieve significant diversity in this biologically important template.
- Liu, Kevin G.,Lo, Jennifer R.,Robichaud, Albert J.
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experimental part
p. 573 - 577
(2010/09/05)
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- SPIROINDOLINES AS MODULATORS OF CHEMOKINE RECEPTORS
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The present invention relates to a compound of the following formula: where R1-R6, R10, Y, n, m, p, and q are as defined herein. Compounds and compositions of the present invention are useful for the treatment of diseases
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Page/Page column 22
(2009/01/24)
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- Synthesis and structure based optimization of novel Akt inhibitors
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Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced pot
- Lippa, Blaise,Pan, Gonghua,Corbett, Matthew,Li, Chao,Kauffman, Goss S.,Pandit, Jayvardhan,Robinson, Shaughnessy,Wei, Liuqing,Kozina, Ekaterina,Marr, Eric S.,Borzillo, Gary,Knauth, Elisabeth,Barbacci-Tobin, Elsa G.,Vincent, Patrick,Troutman, Merin,Baker, Deborah,Rajamohan, Francis,Kakar, Shefali,Clark, Tracey,Morris, Joel
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body text
p. 3359 - 3363
(2009/04/05)
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- N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y1 receptor which can be used as medicaments.
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Page/Page column 73
(2010/11/25)
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- Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.
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Page/Page column 54
(2008/06/13)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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Compounds of formula (I) are described herein The compounds can be used, for example, to modulate growth hormone secretagogue receptor (GHS-R). In some instances, the compounds can be used to treat obesity.
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Page/Page column 89; 90
(2008/06/13)
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- SULFONAMIDES AND USES THEREOF
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Compounds of formulas (I), (II), (III), and (IV) and methods of treating disorders by administering a compound of formula (I), (II), (III), or (IV) are described herein. Examples of disorders include neoplastic disorders, fat-cell related disorders, neurodegenerative disorders, and metabolic disorders.
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Page/Page column 85
(2010/02/14)
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- A convenient synthesis of 1′-H-spiro-(indoline-3,4′-piperidine) and its derivatives
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A simple synthetic route has been developed to prepare 1′-H- spiro(indoline-3,4′-piperidine) (1d). Dialkylation of 2- fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′-N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds (1a, 1b and 1d) can be utilized as templates to synthesize compounds for GPCR targets.
- Xie, Jian-Shu,Huang, Charles Q.,Fang, Yan-Yan,Zhu, Yun-Fei
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p. 4875 - 4878
(2007/10/03)
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- Synthesis of the orally active spiroindoline-based Growth Hormone Secretagogue, MK-677
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The preparation of the Merck Growth Hormone Secretagogue; MK-677 is described. A Fischer indole/reduction based strategy provides the novel spiroindoline nucleus of this potent compound. This optimized sequence necessitates the isolation of only one intermediate 10 and provides MK-677 in 48% overall yield from isonipecotic acid 3.
- Maligres, Peter E.,Houpis, Ioannis,Rossen, Kai,Molina, Audrey,Sager, Jess,Upadhyay, Veena,Wells, Kenneth M.,Reamer, Robert A.,Lynch, Joseph E.,Askin, David,Volante,Reider, Paul J.,Houghton, Peter
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p. 10983 - 10992
(2007/10/03)
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