- A multifunctional reagent designed for the site-selective amination of pyridines
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We report the development of a multifunctional reagent for the direct conversion of pyridines to Boc-protected 2-aminopyridines with exquisite site selectivity and chemoselectivity. The novel reagent was prepared on 200-g scale in a single step, reacts in the title reaction under mild conditions without precautions toward air or moisture, and is tolerant of nearly all common functionality. Experimental and in situ spectroscopic monitoring techniques provide detailed insights and unexpected findings for the unique reaction mechanism.
- Fier, Patrick S.,Kim, Suhong,Cohen, Ryan D.
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p. 8614 - 8618
(2020/06/05)
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- SUBSTITUTED NITROGEN CONTAINING COMPOUNDS
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Disclosed are compounds of Formula (I): or a salt thereof, Formula (II) wherein R1 is: or; each W is independently NR1b or O; Z is a bond or CHR1d; and R1, R2, Rd, R3a, R3b, L1, B, V, Y, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of ROMK, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating cardiovascular diseases.
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Page/Page column 308; 309
(2019/01/05)
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- Selective IKur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
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We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2′ position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.
- Gunaga, Prashantha,Lloyd, John,Mummadi, Somanadham,Banerjee, Abhisek,Dhondi, Naveen Kumar,Hennan, James,Subray, Veena,Jayaram, Ramya,Rajugowda, Nagendra,Umamaheshwar Reddy, Kommuri,Kumaraguru, Duraimurugan,Mandal, Umasankar,Beldona, Dasthagiri,Adisechen, Ashok Kumar,Yadav, Navnath,Warrier, Jayakumar,Johnson, James A.,Sale, Harinath,Putlur, Siva Prasad,Saxena, Ajay,Chimalakonda, Anjaneya,Mandlekar, Sandhya,Conder, MaryLee,Xing, Dezhi,Gupta, Arun Kumar,Gupta, Anuradha,Rampulla, Richard,Mathur, Arvind,Levesque, Paul,Wexler, Ruth R.,Finlay, Heather J.
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supporting information
p. 3795 - 3803
(2017/05/19)
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- Discovery of a potent, cell penetrant, and selective p300/CBP-associated factor (PCAF)/general control nonderepressible 5 (GCN5) bromodomain chemical probe
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P300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
- Humphreys, Philip G.,Bamborough, Paul,Chung, Chun-Wa,Craggs, Peter D.,Gordon, Laurie,Grandi, Paola,Hayhow, Thomas G.,Hussain, Jameed,Jones, Katherine L.,Lindon, Matthew,Michon, Anne-Marie,Renaux, Jessica F.,Suckling, Colin J.,Tough, David F.,Prinjha, Rab K.
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supporting information
p. 695 - 709
(2017/02/05)
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- Pleuromutilin derivatives such, its pharmaceutical composition and synthetic method and use thereof
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The present invention relates to a class of pleuromytilin compounds represented by the following general formula (I), pharmaceutically acceptable salts and preparation methods thereof, and compositions comprising the compound represented by the general fo
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- ISOCHROMENE DERIVATIVES AS PHOSPHOINOSITIDE 3-KINASES INHIBITORS
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The invention relates to compounds inhibiting phosphoinositide 3-kinases (PI3K), to pharmaceutical compositions comprising them and therapeutic use thereofin the treatment of disorders associated with PI3K enzymes.
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Page/Page column 141
(2015/07/07)
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- ISOCHROMENE DERIVATIVES AS PHOSHOINOSITIDE 3-KINASES INHIBITORS
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Compounds of formula (I) described herein are useful for inhibiting phosphoinositide 3-kinases (PI3K) and the treatment of disorders associated with PI3K enzymes.
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-
Paragraph 0870; 0871; 0872
(2015/06/24)
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- Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis
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A single set of conditions consisting of a palladium catalyst, a commercially available ligand, and a base, allow for several types of C-N bond constructions to be conducted in water with the aid of a commercially available "designer" surfactant (TPGS-750-M). Products containing a protected NH2 group in the form of a carbamate, sulfonamide, or urea can be fashioned starting with aryl or heteroaryl bromides, iodides, and in some cases, chlorides, as substrates. Reaction temperatures are in the range of room temperature to, at most, 50 °C, and result in essentially full conversion and good isolated yields.
- Isley, Nicholas A.,Dobarco, Sebastian,Lipshutz, Bruce H.
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supporting information
p. 1480 - 1488
(2014/03/21)
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- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
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Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl.
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Page/Page column 101
(2014/03/25)
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- 1H-PYRAZOLO[3,4-B]PYRIDINES AND THERAPEUTIC USES THEREOF
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Provided herein are compounds according to Formulas (I) or (II) and pharmaceutically acceptable salts thereof, and compositions comprising the same, for use in various methods, including treating cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis, idiopathic pulmonary fibrosis and neurological conditions/disorders/diseases.
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Paragraph 0515
(2013/11/19)
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- QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
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A compound of formula (I) wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.
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Page/Page column 247-248
(2011/04/14)
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- Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2- ethanediones: Potent, selective carboxylesterase inhibitors
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Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic,
- Young, Brandon M.,Hyatt, Janice L.,Bouck, David C.,Chen, Taosheng,Hanumesh, Parimala,Price, Jeanine,Boyd, Vincent A.,Potter, Philip M.,Webb, Thomas R.
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supporting information; experimental part
p. 8709 - 8715
(2011/02/23)
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- FUSED BICYCLIC COMPOUNDS AS INHIBITORS FOR PI3 KINASE
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The invention relates to compounds of formula (I) for the regulation of phosphoinositides 3-kinases activity and related diseases.
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Page/Page column 138
(2010/09/18)
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- Pyrrolopyrimidines and Pyrrolopyridines
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Compounds of formula I in free or salt or solvate form, wherein X, T1, T3 and T4 have the meanings as indicated in the specification, are useful for treating diseases mediated by the ALK-5 and/or ALK-4 receptor. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 55
(2009/07/25)
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- Aminopyrimidine Derivatives With Tie2 Inhibiting Activity
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The invention relates to a compound of the Formula I or salt thereof wherein Rx, Ry, Rx, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.
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Page/Page column 31
(2008/12/07)
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- PYRROLOTRIAZINE KINASE INHIBITORS
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The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of Trk receptors such as TrkA, TrkB, TrkC or Flt-3 thereby making them useful as antiproliferative agents.
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Page/Page column 24
(2008/06/13)
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- PYRIMIDINE COMPOUNDS HAVING TIES (TEK) INHIBITORY ACTIVITY
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The invention relates to a compound of the Formula (I) or salt thereof wherein Rx, Ry, Rz, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.
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Page/Page column 107
(2008/06/13)
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- Synthesis and identification of [1,3,5]triazine-pyridine biheteroaryl as a novel series of potent cyclin-dependent kinase inhibitors
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On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and
- Kuo, Gee-Hong,DeAngelis, Alan,Emanuel, Stuart,Wang, Aihua,Zhang, Yan,Connolly, Peter J.,Chen, Xin,Gruninger, Robert H.,Rugg, Catherine,Fuentes-Pesquera, Angel,Middleton, Steven A.,Jolliffe, Linda,Murray, William V.
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p. 4535 - 4546
(2007/10/03)
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- PYRIMIDINES WITH TIE2 (TEK) ACTIVITY
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The invention relates to a compound of the Formula (I). or salt thereof wherein R1, R2, R3, R4, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm-blooded animal. The invention also relates to processes for the preparation of said compounds.
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Page/Page column 150
(2010/02/12)
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- Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors
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Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth facto
- Kuo, Gee-Hong,Wang, Aihua,Emanuel, Stuart,DeAngelis, Alan,Zhang, Rui,Connolly, Peter J.,Murray, William V.,Gruninger, Robert H.,Sechler, Jan,Fuentes-Pesquera, Angel,Johnson, Dana,Middleton, Steven A.,Jolliffe, Linda,Chen, Xin
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p. 1886 - 1900
(2007/10/03)
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- SUBSTITUTED TRIAZINE KINASE INHIBITORS
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The present invention provides substituted 1,3,5-triazine compounds as kinase inhibitors and a method for treating or ameliorating a kinase mediated disorder.
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- NOVEL AMIDE COMPOUNDS
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A compound of the formula (I):R1-A-X-NHCO-Y-R2 ???whereinR1 is heterocyclic group which may have suitable substituents, or phenyl which may have suitable substituents,R2 is condensed phenyl which may have suitable substituents, phenyl which may have suitable substituents, or thienyl which may have suitable substituents,A is a group of the formula:-(CH2)t-(O)m- or in which R3 and R4 are each hydrogen or linked together to form imino,R5 is hydrogen or lower alkyl,t is 0, 1 or 2,p, m and n are each 0 or 1,X is phenylene which may have suitable substituents, or bivalent heterocyclic group containing nitrogen which may have suitable substituents,Y is bond, lower alkylene, or lower alkenylene, and a salt thereof.
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