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WO2000040581A1 - Derives de la 3,4-dihydro-2h benzo[1,4]oxazine - Google Patents

Derives de la 3,4-dihydro-2h benzo[1,4]oxazine Download PDF

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Publication number
WO2000040581A1
WO2000040581A1 PCT/US2000/000347 US0000347W WO0040581A1 WO 2000040581 A1 WO2000040581 A1 WO 2000040581A1 US 0000347 W US0000347 W US 0000347W WO 0040581 A1 WO0040581 A1 WO 0040581A1
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WO
WIPO (PCT)
Prior art keywords
compound
dihydro
hydrogen
pharmaceutically acceptable
benzo
Prior art date
Application number
PCT/US2000/000347
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English (en)
Inventor
Richard Eric Mewshaw
Uresh Shantilal Shah
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American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU24943/00A priority Critical patent/AU2494300A/en
Publication of WO2000040581A1 publication Critical patent/WO2000040581A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • SSRIs selective serotonin reuptake inhibitors
  • WO 8907596-A discloses the preparation of compounds having the following formula which are active in a variety of CNS disorders, including depression and schizophrenia.
  • U.S. Patent No. 4,612,312 discloses compounds of the following formula as anxiolytic and antihypertensive agents.
  • the present invention relates to a new class of molecules which have the ability to act at the 5-HT 1 A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
  • the compounds of this invention are 3,4-dihydro-2H-benzo[l,4]oxazine derivatives represented by Formula I:
  • R is hydrogen or halogen
  • R is hydrogen, alkoxy or carboximide
  • R 3 is hydrogen, alkyl, alkylaryl, aryl or substituted aryl
  • R 4 is hydrogen, CN, halogen or carboximide
  • X is CH or N; or a pharmaceutically acceptable salt thereof.
  • R. is hydrogen
  • R 2 is alkoxy or hydrogen
  • R 3 is hydrogen, alkyl or alkylaryl; and/or R 4 is halogen or hydrogen; and/or
  • X is CH or N; or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are: 2-[4-(5-Fluoro-lH-indol-3-yl)-3,6-dihydro-2H-pyridin-l-ylmethyl]-8-methoxy-3,4- dihydro-2H-benzo[ 1 ,4] oxazine;
  • alkyl and alkoxy are meant to include both straight and branched carbon chains containing 1-6 carbon atoms.
  • aryl is meant to include aromatic radicals of 6-12 carbon atoms.
  • halogen is meant to include fluorine, chlorine, bromine, and iodine.
  • the compounds of this Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base.
  • Such salts prepared by methods well known to the art are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene- sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • the compounds of the present invention may be prepared by any suitable method
  • Ri is hydrogen or halogen
  • R is hydrogen, alkoxy or carboximide
  • R 3 is hydrogen, alkyl, arylalkyl, aryl or substituted aryl
  • R-i is hydrogen, CN, halogen or carboximide
  • X is CH or N; or a pharmaceutically acceptable salt thereof, which comprises one of the following:
  • Ri, R 2 , R» and X are as defined above and P is an amino protecting group to give a compound of formula I wherein R 3 is hydrogen; or
  • Rj and R 2 are as defined above
  • A is a leaving group selected from halogen or an organic sulphonyloxy group, e.g. aryl or alkyl sulphonyloxy group such as tosyloxy
  • R 5 is alkyl, arylalkyl, aryl, substituted aryl or an amino protecting group P as defined above, with a compound of formula IV
  • R-j and X are as defined above, and if required removing a protecting group P if present, to give a compound of formula I; or
  • the removal of a protecting group can be achieved by methods known in the art, e.g. when the protecting group is BOC it can be removed by using trifluoroacetic acid as shown hereinafter in Examples 1 and 5.
  • the compounds of formula I can possess at least one asymmetric centre and accordingly the compounds may exist and be isolated in a number of optically active stereoisomeric forms.
  • This invention encompasses the compounds of formula I in any optically active form or mixtures thereof eg, racemates. Standard separation techniques may be used to isolate particular enantiomeric or diastereomeric forms. For example a racemic mixture may be converted to a mixture of optically active diastereoisomers by reaction with a single enantiomer of a 'resolving agent' (for example by diastereomeric salt formation or formation of a covalent bond).
  • optically active diastereoisomers may be separated by standard techniques (e.g crystallisation or chromatography) and individual optically active diastereoisomers then treated to remove the 'resolving agent' thereby releasing the single enantiomer of the compound of the invention.
  • Chiral chromatography using a chiral support, eluent or ion pairing agent may also be used to separate enantiomeric mixtures directly.
  • ⁇ -amino protecting groups are well known in the art and may be (1) the acyl type protecting groups illustrated by the following: formyl, trifluoroacetyl, phthalyl, /?-toluenesulfonyl (tosyl) and o-nitrophenylsulfenyl; (2) aromatic urethane type protecting groups illustrated by benzyloxycarbonyl and substituted benzyloxycarbonyl such as -chlorobenzyloxycarbonyl, ?-nitrobenzylcarbonyl; (3) aliphatic urethane protecting groups illustrated by tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, amyloxycarbonyl; (4) cycloalkyl urethane type protecting groups illustrated by cyclopentyloxycarbonyl, adamantyl
  • R is R 3 except hydrogen or a protecting group
  • INTERMEDIATE 4 (8-Methoxy-3,4-dihydro-2H-benzo[l,4]oxazin-2-yl)-methanol A mixture of Intermediate 3 (2.3 g, 9.2 mmol) in tetrahydrofuran (200 ml) was stirred at room temperature and lithium borohydride (0.9 g, 42 mmol) was added to above solution in small portions. The reaction mixture was heated to 65°C for 20 hours. The excess lithium borohydride was destroyed by the cautious addition of water. The mixture was concentrated and extracted with ethyl acetate and washed with brine.
  • the oxalate salt was prepared in ethanol: mp 162-166 °C. Elemental analysis for C 23 H 24 FN 3 O 2 -0.8C 2 H 2 O 4 Calc'd: C, 63.48; H, 5.54; N, 9.03
  • the activity of the present compounds is demonstrated by the following standard pharmacological test procedures.
  • the PCR cloning of the human 5-HT 1A receptor subtype from a human genomic library has been described previously by Chanda et al., Mol. Pharmacol.. 43:516 (1993).
  • a stable Chinese hamster ovary cell line expressing the human 5-HT 1A receptor subtype (5-HT 1A .CHO cells) was employed throughout this study. Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin/ streptomycin.
  • Cells were grown to 95-100% confluency as a monolayer before membranes were harvested for binding studies. Cells were gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris; pH 7.5). The resulting pellets were aliquoted and placed at -80 # C. On the day of assay, the cells were thawed on ice, and resuspended in buffer. Studies were conducted using [ 3 H]8-OH-DPAT as the radioligand. The binding assay was performed in 96 well microtiter plates in a final total volume of 250 ⁇ L of buffer.
  • 5-HT 1A cloned receptor membrane fragments (as used for 5-HT 1A receptor binding assays) were stored at -70 °C until needed. When needed, membranes were rapidly thawed, centrifuged at 40,000 x g for 10 minutes and resuspended at 4 °C for 10 minutes in assay buffer (25 mM HEPES, 3 mM MgCl,, 100 mM NaCl, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0).
  • assay buffer 25 mM HEPES, 3 mM MgCl, 100 mM NaCl, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0.
  • Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
  • the compounds of the present invention may be administered orally or parentally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
  • the variables involved include the specific psychosis and the size, age and response pattern of the patient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) dans laquelle R1 représente un hydrogène ou un halogène, R2 représente un hydrogène, un alcoxyle ou un carboximide, R3 représente un hydrogène, un alkyle, un alkylaryle, un aryle ou un aryle substitué, R4 représente un hydrogène, CN, un halogène ou un carboximide, et X représente CH ou N; ou un sel pharmaceutiquement acceptable de ces composés, qui sont utiles en tant qu'anxiolytiques et/ou anti-dépresseurs.
PCT/US2000/000347 1999-01-07 2000-01-06 Derives de la 3,4-dihydro-2h benzo[1,4]oxazine WO2000040581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24943/00A AU2494300A (en) 1999-01-07 2000-01-06 3,4-dihydro-2h-benzo(1,4)oxazine derivatives

Applications Claiming Priority (2)

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US22683299A 1999-01-07 1999-01-07
US09/226,832 1999-01-07

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
WO2002034754A3 (fr) * 2000-10-26 2002-07-11 Smithkline Beecham Plc Derives de benzoxazinone, leur preparation et utilisation
WO2003006455A1 (fr) * 2001-07-11 2003-01-23 Eli Lilly And Company Composes pharmaceutiques a activite de recepteur de serotonine
WO2003068772A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique
WO2003091248A1 (fr) * 2002-04-23 2003-11-06 Glaxo Group Limited Derive de benzoxazinone
US6777437B2 (en) 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
WO2004106298A1 (fr) * 2003-05-30 2004-12-09 Janssen Pharmaceutica N.V. Derive d'indole a activite antipsychotique amelioree
US7635696B2 (en) 2004-11-26 2009-12-22 Janssen Pharmaceutica N.V. Isoxazoline-indole derivatives with an improved antipsychotic and anxiolytic activity
US8188281B2 (en) 2004-03-30 2012-05-29 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10377746B2 (en) 2015-11-06 2019-08-13 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10457667B2 (en) 2015-11-06 2019-10-29 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10519140B2 (en) 2015-11-06 2019-12-31 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10710985B2 (en) 2015-11-06 2020-07-14 Hoffmann-La Roche Inc. Indolin-2-one derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989007596A1 (fr) * 1988-02-15 1989-08-24 Farmitalia Carlo Erba S.R.L. Nouveaux derives de 1,4-benzoxazine et de 1,4-benzothiazine et procede servant a leur preparation
WO1999051592A1 (fr) * 1998-04-08 1999-10-14 American Home Products Corporation Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989007596A1 (fr) * 1988-02-15 1989-08-24 Farmitalia Carlo Erba S.R.L. Nouveaux derives de 1,4-benzoxazine et de 1,4-benzothiazine et procede servant a leur preparation
WO1999051592A1 (fr) * 1998-04-08 1999-10-14 American Home Products Corporation Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A.-S. BOURLOT ET AL.: "New substituted 1,4-benzoxazine derivatives with potential intracellular calcium activity", JOURNAL OF MEDICINAL CHEMISTRY., vol. 41, no. 17, 1998, AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 3142 - 3158, XP002136635, ISSN: 0022-2623 *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
US7276508B2 (en) 2000-06-14 2007-10-02 H. Lundbeck A/S Indole derivatives useful for the treatment of CNS disorders
US6890916B2 (en) 2000-06-14 2005-05-10 H. Lundbeck A/S Indole derivatives useful for the treatment of CNS disorders
US6939871B2 (en) 2000-10-26 2005-09-06 Smithkline Beecham P.L.C. Benzoxazinone derivatives, their preparation and use
WO2002034754A3 (fr) * 2000-10-26 2002-07-11 Smithkline Beecham Plc Derives de benzoxazinone, leur preparation et utilisation
US6777437B2 (en) 2001-03-29 2004-08-17 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
US6822100B2 (en) 2001-03-29 2004-11-23 Bristol-Myers Squibb Company Cyclopropylindole derivatives as selective serotonin reuptake inhibitors
WO2003006455A1 (fr) * 2001-07-11 2003-01-23 Eli Lilly And Company Composes pharmaceutiques a activite de recepteur de serotonine
WO2003068772A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique
US7244726B2 (en) 2002-02-18 2007-07-17 Glaxo Group Limited Heterocyclic compounds possessing affinity at 5HT1 -type receptors and use thereof in therapy
WO2003091248A1 (fr) * 2002-04-23 2003-11-06 Glaxo Group Limited Derive de benzoxazinone
WO2004106346A1 (fr) * 2003-05-30 2004-12-09 Janssen Pharmaceutica N.V. Derives d'indole avec activite antipsychotique amelioree
WO2004106298A1 (fr) * 2003-05-30 2004-12-09 Janssen Pharmaceutica N.V. Derive d'indole a activite antipsychotique amelioree
US8188281B2 (en) 2004-03-30 2012-05-29 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8987454B2 (en) 2004-03-30 2015-03-24 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8501446B2 (en) 2004-03-30 2013-08-06 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8722889B2 (en) 2004-03-30 2014-05-13 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US7635696B2 (en) 2004-11-26 2009-12-22 Janssen Pharmaceutica N.V. Isoxazoline-indole derivatives with an improved antipsychotic and anxiolytic activity
US8962642B2 (en) 2006-12-21 2015-02-24 Vertex Pharmaceuticals Incorporated 5-cyano-4- (pyrrolo [2,3B] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
US8530489B2 (en) 2006-12-21 2013-09-10 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9518056B2 (en) 2009-06-17 2016-12-13 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10874673B2 (en) 2009-06-17 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9808459B2 (en) 2009-06-17 2017-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10039762B2 (en) 2009-06-17 2018-08-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10875855B2 (en) 2011-08-01 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9394302B2 (en) 2011-08-01 2016-07-19 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9908878B2 (en) 2011-08-01 2018-03-06 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10640501B2 (en) 2013-11-13 2020-05-05 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US11345700B2 (en) 2013-11-13 2022-05-31 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10377746B2 (en) 2015-11-06 2019-08-13 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10457667B2 (en) 2015-11-06 2019-10-29 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10519140B2 (en) 2015-11-06 2019-12-31 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10710985B2 (en) 2015-11-06 2020-07-14 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US11066393B2 (en) 2015-11-06 2021-07-20 Hoffmann-La Roche Inc. Indolin-2-one derivatives

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