- Optimization of Orally Bioavailable PI3KδInhibitors and Identification of Vps34 as a Key Selectivity Target
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Optimization of a lead series of PI3Kδinhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδover Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
- Henley, Zo? A.,Amour, Augustin,Barton, Nick,Bantscheff, Marcus,Bergamini, Giovanna,Bertrand, Sophie M.,Convery, Máire,Down, Kenneth,Dümpelfeld, Birgit,Edwards, Chris D.,Grandi, Paola,Gore, Paul M.,Keeling, Steve,Livia, Stefano,Mallett, David,Maxwell, Aoife,Price, Mark,Rau, Christina,Reinhard, Friedrich B. M.,Rowedder, James,Rowland, Paul,Taylor, Jonathan A.,Thomas, Daniel A.,Hessel, Edith M.,Hamblin, J. Nicole
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supporting information
p. 638 - 655
(2020/02/04)
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- INHIBITOR OF BTK AND MUTANTS THEREOF
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The disclosure includes compounds of Formula (I) (1) wherein Q0, Q1, Q2, Q3, Q4, Z, W, i, j, m, n, Warhead, R0, R1, R3, R4, R5, R6, and R7, are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.
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- Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions
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We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
- Yu, Wensheng,Tong, Ling,Selyutin, Oleg,Chen, Lei,Hu, Bin,Zhong, Bin,Hao, Jinglai,Ji, Tao,Zan, Shuai,Yin, Jingjun,Ruck, Rebecca T.,Curry, Stephanie,McMonagle, Patricia,Agrawal, Sony,Rokosz, Laura,Carr, Donna,Ingravallo, Paul,Bystol, Karin,Lahser, Frederick,Liu, Rong,Chen, Shiying,Feng, Kung-I,Cartwright, Mark,Asante-Appiah, Ernest,Kozlowski, Joseph A.
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p. 3984 - 4003
(2018/05/14)
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- A Scalable Synthesis of (R,R)-2,6-Dimethyldihydro-2H-pyran-4(3H)-one
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A scalable synthesis of (R,R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one is reported. Key to this strategy is the Ti(OiPr)4-catalyzed Kulinkovich cyclopropanation of silyl protected (R)-ethyl 3-hydroxybutanoate, and subsequent oxidative fragmentati
- Young, Ian S.,Haley, Matthew W.,Tam, Annie,Tymonko, Steven A.,Xu, Zhongmin,Hanson, Ronald L.,Goswami, Animesh
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p. 1360 - 1368
(2015/11/02)
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- PIPERAZINE DERIVATIVES AS HIV PROTEASE INHIBITORS
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The present invention is directed to compounds of Formula I pharmaceutical compositions comprising the same, and their use in the inhibition of HIV protease, the inhibition of HIV replication, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS.
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- THIAZOLYL-SUBSTITUED TETRACYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Thiazolyl-Substituted Tetracyclic Compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, A', R2R3, R4 and R5 are as defined herein. The present
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Page/Page column 43; 44
(2014/08/06)
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- HETEROCYCLE-SUBSTITUED TETRACYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Heterocycle-Substituted Tetracyclic Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, A', R 2 R 3, R 4 and R are as defined herein. The present i
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- THIOPHENE-SUBSTITUTED TETRACYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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Thiophene-substituted tetracyclic compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein A, A', R2, R3, R4 and R5 are as defined herein. The compositions comprising at least one thiophene-substituted tetracyclic compound, and methods of using the thiophene-substituted tetracyclic compounds for treating or preventing HCV infection in a patient are also provided.
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- APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE AND AUTOIMMUNE DISEASES
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Disclosed herein are compounds that inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases using the compounds.
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Paragraph 0326
(2014/09/30)
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- PHENYL-HETEROARYL AMINE COMPOUNDS AND THEIR USES
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The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I, and pharmaceutical compositions comprising such compounds
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Page/Page column 86
(2012/06/01)
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- 3-(AMINOARYL)-PYRIDINE COMPOUNDS
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The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. Also provided are pharmaceutical compositions containing these compounds and methods of treating a disease or condition mediated by CDK9 using these compounds and compositions.
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Page/Page column 93-94
(2012/06/01)
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- N-ACYL PYRIDINE BIARYL COMPOUNDS AND THEIR USES
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The present invention provides a compound of general formula:wherein Z2-Z6 include one or two nitrogen atoms as described herein, including pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I and isomers thereof, and pharmaceutical compositions comprising such compounds.
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Page/Page column 110
(2012/08/08)
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- PYRIDINE BIARYL AMINE COMPOUNDS AND THEIR USES
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The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I and isomers thereof, and pharmaceutical compositions comprising such compounds.
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Page/Page column 70; 99-100
(2012/08/08)
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- N-ACYL PYRIMIDINE BIARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The present invention provides a compound of the general formula (1): wherein one of X and Y is N and the other is an optionally substituted carbon atom, and Z2-Z5 represent one or two nitrogen atoms, as further described herein, including pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals and as components of pharmaceutical compositions. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds described herein or pharmaceutical compositions comprising such compounds.
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Page/Page column 150-151
(2012/08/08)
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- PYRIMIDINE BIARYL AMINE COMPOUNDS AND THEIR USES
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The present invention provides a pyrimidine compound of formula (I): wherein one of X and Y but not both is N, and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tantomers, diastereomers, deuterated versions, or racemates thereof. These compounds inhibit the activity of CDK9 and are thus useful as pharmaceuticals. Also provided are methods of treating a disease or condition mediated by CDK9 using the compounds of Formula I and isomers thereof, and pharmaceutical compositions comprising such compounds
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Page/Page column 89
(2012/08/08)
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- Heteroaryl Compounds and Their Uses
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The present invention provides a compound of formula (I): and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. Also provided is a method of treating a disease or condition mediated by CDK9.
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Page/Page column 22
(2011/02/25)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of Hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
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Page/Page column 143
(2011/07/07)
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- BICYCLIC HETEROCYCLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Bicyclic Heterocycle Derivatives, compositions comprising a Bicyclic Heterocycle Derivative, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of GPR119 in a patient.
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Page/Page column 192-193
(2009/05/30)
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- INHIBITORS OF SERINE PROTEASES
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The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt or mixtures thereof that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease.
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Page/Page column 302
(2010/11/26)
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- Diastereoselective synthesis of cis-2,6-disubstituted perhydro-4-pyranones using elevated pressure hydrogenation
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A diastereoselective strategy for the synthesis of γ-pyrons was developed, starting from the Mg diacetonedicarboxylate complex. Initial cyclization with suitable anhydrides or acid chlorides, followed by hydrolytic decarboxylation leads to 2,6-disubstitut
- Mihovilovic, Marko D.,Spreitzer, Helmut
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p. 1197 - 1203
(2007/10/03)
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- Synthesis and Conformational Studies of Dipeptides Constrained by Disubstituted 3-(Aminoethoxy)propionic Acid Linkers
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A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have been prepared as potential β-turn mimics. The desired linkers were prepared from disubstituted pyrones, which were coupled with dipeptides and then subjected
- Reddy, D. Srinivasa,Vander Velde, David,Aube, Jeffrey
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p. 1716 - 1719
(2007/10/03)
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- Synthesis and Enantioselective Baeyer-Villiger Oxidation of Prochiral Perhydro-pyranones with Recombinant E. coli Producing Cyclohexanone Monooxygenase
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Recombinant whole cells of Escherichia coli overexpressing Adnetobacter sp. NCIMB 9871 cyclohexanone monooxygenase (E.C. 1.14.13.22) have been utilized for the Baeyer-Villiger oxidation of prochiral perhydro-pyranones. The spatial limitations of the enzym
- Mihovilovic, Marko D.,Rudroff, Florian,Kandioller, Wolfgang,Gr?tzl, Birgit,Stanetty, Peter,Spreitzer, Helmut
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p. 1973 - 1976
(2007/10/03)
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- 7-Methyl-2,3,4,5-tetrahydro-1,4-oxazepin-5-one and the Dioxepinone Analogue: Diastereofacial Selectivity in Catalytic Hydrogenation and the Explanation
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Catalytic hydrogenation of the title compound proceeds from the site anti to the 7-methyl group to give the cis-dimethyl derivative; a possible stereoelectronic effect accounting for this selectivity is proposed based on the conformational analysis of the
- Sato, Masayuki,Kuroda, Hiroshi,Kaneko, Chikara,Furuya, Toshio
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p. 687 - 688
(2007/10/02)
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- Enantiospecific Synthesis of (+)-(2R)- and (-)-(2S)-6-Ethyl-3,4-dihydro-2-methyl-4-oxo-2H-pyran-5-carboxylic Acid
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The two enantiomers (-)-(2S)- and (+)-(2R)-6-ethyl-3,4-dihydro-2-methyl-4-oxo-2H-pyran-5-carboxylic acid ((S)- and (R)-7) have been synthesized from (+)-(3S) and (-)-(3R)-3-hydroxybutanoates, respectively (Scheme 1).By reduction and decarboxylation, the tetrahydro-2H-pyranols (2R,4R,6S)- and (2S,4S,6R)-13, respectively, were obtained with an enantiomeric excess of >/= 93 percent.
- Deschenaux, Pierre-Francois,Kallimopoulos, Thomas,Stoeckli-Evans, Helen,Jacot-Guillarmod, Andre
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p. 731 - 737
(2007/10/02)
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