- Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy
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Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2′ moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
- Dilger, Andrew K.,Pabbisetty, Kumar B.,Corte, James R.,De Lucca, Indawati,Fang, Tianan,Yang, Wu,Pinto, Donald J. P.,Wang, Yufeng,Zhu, Yeheng,Mathur, Arvind,Li, Jianqing,Hou, Xiaoping,Smith, Daniel,Sun, Dawn,Zhang, Huiping,Krishnananthan, Subramaniam,Wu, Dauh-Rurng,Myers, Joseph E.,Sheriff, Steven,Rossi, Karen A.,Chacko, Silvi,Zheng, Joanna J.,Galella, Michael A.,Ziemba, Theresa,Dierks, Elizabeth A.,Bozarth, Jeffrey M.,Wu, Yiming,Crain, Earl,Wong, Pancras C.,Luettgen, Joseph M.,Wexler, Ruth R.,Ewing, William R.
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- One-pot, two-step synthesis of 3,4-dihydroquinazoline-2(1H)-thiones from o-azidobenzenealdehydes, aryl amines and carbon disulfide
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A one-pot, two-step method was developed for the synthesis of 3-aryl-3,4-dihydroquinazoline-2(1H)-thiones involving the reductive amination of o-azidobenzaldehydes and aryl amines followed by the Staudinger-aza-Wittig reaction with CS2.
- Zhang, Wensheng,Li, Yan,Zhou, Hongyan,Su, Xiaoli,Zhang, Xiaofeng,Zhang, Wei
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supporting information
(2021/09/02)
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- 2-[3-(ALKYLSULFONYL)-2H-INDAZOL-2-YL]-3H-IMIDAZO[4,5-B]PYRIDINE DERIVATIVES AND SIMILAR COMPOUNDS AS PESTICIDES
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The invention relates to compounds of the formula (Ia) or (Ib), in which Aa, Ab, Ac, Ad, R1, R10 R11, R12, R13, R14, R15, R16, R17, Q, R4, R5, R
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Paragraph 0746; 0755; 0756
(2019/09/20)
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- Pd-Catalyzed Four-Component Sequential Reaction Delivers a Modular Fluorophore Platform for Cell Imaging
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A Pd-catalyzed cascade reaction of four versatile privileged synthons is described. The sequential reaction involves the formation of five new chemical bonds by concatenating three distinct chemical steps. One of the derivatives exhibited absorption in the visible region, fluorescence with a high quantum yield, and excellent photostability. Its application is explored in live cell imaging, which exhibited cytoplasmic and mitochondrial specific staining with no toxicity.
- Ansari, Arshad J.,Joshi, Gaurav,Sharma, Praveen,Maurya, Antim K.,Metre, Ramesh K.,Agnihotri, Vijai K.,Chandaluri, Chanchayya Gupta,Kumar, Raj,Singh, Sandeep,Sawant, Devesh M.
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p. 3817 - 3825
(2019/03/26)
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- Cycloaddition and Cascade Radical Reactions for the Synthesis of Trifluoromethylated Tetrahydrobenzodiazepin-3-ones
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A reaction sequence involving three-component [3 + 2] cycloaddition of azomethine ylides followed by CuI-catalyzed cascade trifluoromethyl radical addition and cyclization is developed for diastereoselective synthesis of fused-tetrahydrobenzodiazepin-3-ones.
- Muthengi, Alex,Erickson, Jon,Muriph, Rachel E.,Zhang, Wei
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p. 5927 - 5935
(2019/05/01)
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- Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo[1,5-c]quinazolines as potential EGFR inhibitors
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A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC50 2.5 μM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.
- Ansari, Arshad J.,Joshi, Gaurav,Yadav, Umesh Prasad,Maurya, Antim K.,Agnihotri, Vijai K.,Kalra, Sourav,Kumar, Raj,Singh, Sandeep,Sawant, Devesh M.
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- FACTOR XIA NEW MACROCYCLE BEARING A NON-AROMATIC P2' GROUP
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 77-78
(2017/02/24)
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- NOVEL SUBSTITUTED GLYCINE DERIVED FXIA INHIBITORS
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The present invention provides compounds of Formula (I): [INSERT CHEMICAL STRUCTURE HERE] (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 85
(2017/02/28)
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- DIAMIDE MACROCYCLES AS FACTOR XIA INHIBITORS
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 99
(2017/01/02)
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- Metal-Free Radical Oxidative Cyclization of o-Azidoaryl Acetylenic Ketones with Sulfinic Acids To Access Sulfone-Containing 4-Quinolones
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A novel one-pot synthesis of sulfone-containing 4-quinolones with easily available sulfinic acids as sulfonylating precursors is described. This reaction is characterized by mild reaction conditions, high functional-group tolerance and amenability to gram-scale synthesis.
- Zhou, Nengneng,Yan, Zhongfei,Zhang, Honglin,Wu, Zhongkai,Zhu, Chengjian
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p. 12181 - 12188
(2016/12/23)
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- Synthesis of 2,3-Disubstituted Quinolines via Ketenimine or Carbodiimide Intermediates
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Cyclopenta[b]quinolines and cyclohexa[b]quinolines were prepared via the reactions of α-diazo ketones with N-(2-cyclopropylidenemethylphenyl)phosphanimines and N-(2-cyclobutylidenemethylphenyl) phosphanimine, respectively. The reaction proceeds in a cascade involving ketenimine formation, 6 π-electron ring closure, and 1,3-alkyl shift. A similar approach was developed for the synthesis of dihydropyrrolo-[2,3-b]quinolines from N-(2-cyclopropylidenemethylphenyl)phosphanimines and isocyanates.
- Zhao, Hongyang,Xing, Yanpeng,Lu, Ping,Wang, Yanguang
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supporting information
p. 15144 - 15150
(2016/10/11)
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- MACROCYCLIC FACTOR XIA INHIBITORS CONDENSED WITH HETEROCYCLES
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The present invention provides compounds of Formula (Ia): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.
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Page/Page column 79
(2015/09/23)
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- Diversity Oriented Synthesis of Indoloazepinobenzimidazole and Benzimidazotriazolobenzodiazepine from N1-Alkyne-1,2-diamines
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A one-pot protocol for the diversity oriented synthesis of two N-polyheterocycles indoloazepinobenzimidazole and benzimidazotriazolobenzodiazepine from a common N1-alkyne-1,2-diamine building block is described. The approach involves sequential formation of benzimidazole through cyclocondensation and oxidation, which is followed by the formation of either an azepine ring (through alkyne activation and 6-endo-dig cyclization, 1,2-migration with ring expansion, and re-aromatization), or diazepine and triazole rings through 1,3-dipolar cycloaddition.
- Kumar, Ravi,Arigela, Rajesh K.,Samala, Srinivas,Kundu, Bijoy
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p. 18828 - 18833
(2016/01/26)
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- OPHA (oxidation-passerini-hydrolysis-alkylation) strategy: A four-step, one-pot improvement of the alkylative passerini reaction
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Multicomponent reactions are often recognized for their efficiency and convergency, if compared with multistep organic synthesis. Nevertheless, we here demonstrate that a four-step-one-pot approach (named OPHA strategy for the initials of the four steps involved) is not only able to afford compounds that could not be obtained by an alkylative Passerini reaction but also capable of generating them with minimal loss of atoms and high operational simplicity, as in a typical multicomponent approach.
- Moliner, Fabio De,Bigatti, Martina,Banfi, Luca,Riva, Renata,Basso, Andrea
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supporting information
p. 2280 - 2283
(2014/05/06)
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- Rh2(II)-catalyzed nitro-group migration reactions: Selective synthesis of 3-nitroindoles from β-nitro styryl azides
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Rhodium carboxylate complexes (1 mol %) catalyze the migration of electron-withdrawing groups to selectively produce 3-substituted indoles from β-substituted styryl azides. The relative order of migratorial aptitude for this transformation is ester ? amide H sulfonyl benzoyl ? nitro.
- Stokes, Benjamin J.,Liu, Sheng,Driver, Tom G.
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supporting information; experimental part
p. 4702 - 4705
(2011/05/16)
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- A general and efficient approach to 2H-indazoles and 1H-pyrazoles through copper-catalyzed intramolecular N-N bond formation under mild conditions
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A new efficient copper-catalyzed intramolecular amination reaction has been developed to readily synthesise a wide variety of multi-substituted 2H-indazole and 1H-pyrazole derivatives from easily accessible starting materials under mild conditions. A highly selective ligand for estrogen receptor β was prepared in three steps by employing this method. The Royal Society of Chemistry 2011.
- Hu, Jiantao,Cheng, Yongfeng,Yang, Yiqing,Rao, Yu
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p. 10133 - 10135
(2011/10/09)
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- A method for the synthesis of substituted quinolines via electrophilic cyclization of 1-azido-2-(2-propynyl)benzene
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(Chemical Equation Presented) A new and efficient strategy for the synthesis of substituted quinolines via electrophilic cyclization is developed. The intramolecular cyclization of 1-azido-2-(2-propynyl)benzene 1 proceeds smoothly in the presence of electrophilic reagents (I2, Br 2 , ICl, NBS, NIS, and HNTf2) in CH3NO 2 at room temperature or in the presence of catalytic amounts of AuCl3/AgNTf2 in THF at 100 °C to afford the corresponding quinolines 2 in good to high yields. In the case of the electrophilic reagents, E of 2 is either I, Br, orH, depending on the reagent type, while E of 2 is H in the case of the electrophilic catalyst. 2010 American Chemical Society.
- Huo, Zhibao,Gridnev, Ilya D.,Yamamoto, Yoshinori
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supporting information; experimental part
p. 1266 - 1270
(2010/04/29)
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