- Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon
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Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.
- Caiger, Lewis,Constantin, Timothée,Douglas, James J.,Juliá, Fabio,Leonori, Daniele,Sheikh, Nadeem S.,Sinton, Conar
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p. 10448 - 10454
(2021/08/20)
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- PYRIMIDINYL GROUP-CONTAINING TRICYCLIC COMPOUND SERVING AS C-MET INHIBITOR
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Disclosed are a pyrimidinyl group-containing tricyclic compound and applications thereof in preparing a cancer-treating medicament. Specifically disclosed are a compound as represented by formula (I), a pharmaceutically acceptable salt of same, or an isomer thereof.
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Paragraph 0563-0565
(2021/12/18)
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- Generation of highly potent DYRK1A-dependent inducers of human β-Cell replication via Multi-Dimensional compound optimization
-
Small molecule stimulation of β-cell regeneration has emerged as a promising therapeutic strategy for diabetes. Although chemical inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is sufficient to enhance β-cell replicat
- Allegretti, Paul A.,Horton, Timothy M.,Abdolazimi, Yassan,Moeller, Hannah P.,Yeh, Benjamin,Caffet, Matthew,Michel, Guillermina,Smith, Mark,Annes, Justin P.
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supporting information
(2019/12/09)
-
- Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease
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To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.
- Leonard, Kristi A.,Madge, Lisa A.,Krawczuk, Paul J.,Wang, Aihua,Kreutter, Kevin D.,Bacani, Genesis M.,Chai, Wenying,Smith, Russell C.,Tichenor, Mark S.,Harris, Michael C.,Malaviya, Ravi,Seierstad, Mark,Johnson, Marguerite E.,Venable, Jennifer D.,Kim, Suzie,Hirst, Gavin C.,Mathur, Ashok S.,Rao, Tadimeti S.,Edwards, James P.,Rizzolio, Michele C.,Koudriakova, Tatiana
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p. 2915 - 2929
(2020/04/08)
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- D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine
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Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-bi
- Shen, Yudao,McCorvy, John D.,Martini, Michael L.,Rodriguiz, Ramona M.,Pogorelov, Vladimir M.,Ward, Karen M.,Wetsel, William C.,Liu, Jing,Roth, Bryan L.,Jin, Jian
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p. 4755 - 4771
(2019/05/08)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
- -
-
Paragraph 1990; 1992
(2019/07/10)
-
- Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases
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Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
- Bach, Jordi,Eastwood, Paul,González, Jacob,Gómez, Elena,Alonso, Juan Antonio,Fonquerna, Silvia,Lozoya, Estrella,Orellana, Adela,Maldonado, Mónica,Calaf, Elena,Albertí, Joan,Pérez, Juan,Andrés, Ana,Prats, Neus,Carre?o, Cristina,Calama, Elena,De Alba, Jorge,Calbet, Marta,Miralpeix, Montserrat,Ramis, Isabel
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p. 9045 - 9060
(2019/11/03)
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- NOVEL JAK1 SELECTIVE INHIBITORS AND USES THEREOF
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The new 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives are selective Jak1 kinase inhibitors useful in treating disorders related to Jak1 activities such as autoimmune diseases or disorders, inflammatory diseases or disorders, and cancer or neoplastic di
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Page/Page column 44; 45
(2018/04/21)
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- 1,3 DI-SUBSTITUTED CYCLOBUTANE OR AZETIDINE DERIVATIVES AS HEMATOPOIETIC PROSTAGLANDIN D SYNTHASE INHIBITORS
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A compound of formula (I), wherein R, R1, R2, R3, Y, Y1, a, X, and Z are as defined herein. The compounds of the present invention are inhibitors of hematopoietic prostaglandin D synthase (H-PGDS) and can be useful in the treatment of Duchenne Muscular Dystrophy. 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 H-PGDS activity and treatment of disorders 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 121-122
(2018/04/27)
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- IMIDAZOPYRROLOPYRIDINE AS INHIBITORS OF THE JAK FAMILY OF KINASES
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2-((1r,4r)-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions mediated by JAK, such as inflammatory bowel disease.
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Page/Page column 109; 110
(2018/07/05)
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- Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains
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A structure-activity relationship study of potent TIQ15-derived CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain was constrained to improve its drug properties. The cyclohexylamino congener 15a was found to be a potent CXCR4 inhi
- Jecs, Edgars,Miller, Eric J.,Wilson, Robert J.,Nguyen, Huy H.,Tahirovic, Yesim A.,Katzman, Brook M.,Truax, Valarie M.,Kim, Michelle B.,Kuo, Katie M.,Wang, Tao,Sum, Chi S.,Cvijic, Mary E.,Schroeder, Gretchen M.,Wilson, Lawrence J.,Liotta, Dennis C.
-
supporting information
p. 89 - 93
(2018/02/19)
-
- Preparation method of trans-4-Boc-aminocyclohexane acetic acid
-
The invention discloses a preparation method of trans-4-Boc-aminocyclohexane acetic acid. The preparation method specifically comprises the steps of reducing carboxyl of trans-4-Boc-aminocyclohexane methanoic acid, so as to obtain trans-4-Boc-aminocyclohexane methanol, reacting with sulfonyl chloride, so as to obtain trans-4-Boc-aminocyclohexane methanol sulphonate, generating substitution reaction with cyanide, so as to obtain trans-4-Boc-aminocyclohexane acetonitrile, and finally carrying out cyan hydrolysis, so as to obtain a target product. The raw materials used in the preparation method are cheap and easily available, the yield is high, and a production process is suitable for large-scale production and can be widely applied to the pharmacy field.
- -
-
Paragraph 0024; 0025
(2017/09/01)
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- METALLO-BETA-LACTAMASE INHIBITORS
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The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
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-
Paragraph 1158
(2016/12/01)
-
- Pyridin-2(1H)-one derivatives useful as medicaments for the treatment of myeloproliferative disorders, transplant rejection, immune-mediated and inflammatory diseases
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New pyridin-2(1h)-one derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 27-28
(2012/12/13)
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- CYCLOHEXYL AMIDE DERIVATIVES AS CRF RECEPTOR ANTAGONISTS
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There are described cydohexyl amide derivatives useful as corticotropin releasing factor (CRF) receptor antagonists
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-
Page/Page column 99-100
(2016/02/02)
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- Heteroaryl imidazolone derivatives as jak inhibitors
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New heteroaryl imidazolone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 67
(2012/01/06)
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- HETEROARYL IMIDAZOLONE DERIVATIVES AS JAK INHIBITORS
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New heteroaryl imidazolone derivatives having the chemical structure of formula (I) disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).
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Page/Page column 123
(2012/01/06)
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- AMINE-DERIVATIVES HAVING NPY Y5 RECEPTOR ANTAGONISTIC ACTIVITY AND THE USES THEREOF
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This invention provides an anorectic or anti-obesity composition comprising a compound of the formula (I): formula (I): a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted lower alkyl,Y is —S(O)n- wherein n is 1 or 2, or —CO—,R2 is hydrogen or lower alkyl, R7 is hydrogen or lower alkyl,X is lower alkylene, lower alkenylene, arylene, cycloalkylene or the like, andZ is lower alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl or the like.
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Page/Page column 22
(2010/12/26)
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- SUBSTITUTED (AZA) -1-METHYL-1H-QUIN0LIN-2-0NES AS ANTIBACTERIALS
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Bicyclic nitrogen containing compounds and their use as antibacterials (Formula I).
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Page/Page column 44
(2010/05/13)
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- AMINE DERIVATIVE HAVING NPY Y5 RECEPTOR ANTAGONIST ACTIVITY
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This invention provides a compound of the formula (I): a pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted lower alkyl, Y is -S(O)n- wherein n is 1 or 2, or -CO-, R2 is hydrogen or lower alkyl,
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Page/Page column 30-31
(2009/02/10)
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- ORGANIC COMPOUNDS
-
The present invention relates to a compound of the formula I wherein R1, R2, R3, R4 and R5 are as defined in the specification, for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (=disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations a compound of that class; a method of treatment comprising administering a compound of that class and a method for its manufacture.
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Page/Page column 38-39
(2009/01/24)
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- BASIC GROUP-CONTAINING COMPOUND AND USE THEREOF
-
A compound represented by general formula (I): a salt thereof, a solvate thereof, or a prodrug thereof wherein all symbols are as defined in the specification has an antagonistic activity against CXCR4 and is therefore useful as a preventive and/or therap
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Page/Page column 100
(2008/12/08)
-
- NITROGENOUS FIVE-MEMBERED RING COMPOUNDS
-
The present invention is to provide an aliphatic nitrogen-containing 5-membered ring compound represented by the formula [I] : wherein symbols in the formula have the following meanings;A: -CH2- or -S-,B: CH or N,R1: H, a lower alkyl group, etc.,X: a single bonding arm, -CO-, -Alk-CO-, -COCH2-, -Alk-O-, -O-CH2-, -SO2-, -S-, -COO-, -CON(R3)-, -Alk-CON(R3)-, -CON(R3)CH2-, -NHCH2-, etc.,R3: hydrogen atom or a lower alkyl group,Alk: a lower alkylene group, andR2: (1) a cyclic group which may be substituted, (2) a substituted amino group, etc., provided that when X is -CO-, then B is N, or a pharmaceutically acceptable salt thereof.
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