Substituted indoline derivatives as dengue viral replication inhibitors
Inventors
Bonfanti, Jean-François • Kesteleyn, Bart Rudolf Romanie • Bardiot, Dorothée Alice Marie-Eve • Marchand, Arnaud Didier M • Coesemans, Erwin • De Boeck, Benoît Christian Albert Ghislain • Raboisson, Pierre Jean-Marie Bernard
Assignees
CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Pharmaceuticals Inc
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Publication Number
US-11053196-B2
Publication Date
2021-07-06
Expiration Date
Abstract
The present invention concerns substituted indoline derivatives, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of the compounds.
Core Innovation
The invention relates to substituted indoline derivatives defined by Formula (I), including any stereochemically isomeric form thereof, and includes pharmaceutically acceptable salts, solvates, and polymorphs. The compounds are described within a general scaffold having A=(a-1) or A=(a-2) and specified substituent patterns for R1, R2, R3, R4, R5, R6 and Z. The compound family includes fluorinated, sulfur-containing, and deuterated variants, and the disclosure includes preparation and characterization of stereochemically defined compounds and intermediates.
The compounds of Formula (I) are described as dengue viral replication inhibitors. The document states that the compounds have potent antiviral activity against all four DENV serotypes and are positioned for medicaments and pharmaceutical compositions for use in preventing and/or treating dengue infections. The description further includes enantiomers, optical rotation embodiments, chiral separation, LC/MS, SFC, 1H NMR, melting points, and chromatographic characterization.
Claims Coverage
The independent claim coverage centers on one Formula (I) compound family with defined substituent alternatives and stereochemically isomeric forms, and extends to pharmaceutically acceptable salts, solvates, or polymorphs. The coverage includes multiple explicit inventive feature groupings for the scaffold, the substituent combinations, and the stereochemical/solid-state forms.
Formula (I) substituted indoline derivative compounds with stereoisomeric forms
A compound of Formula (I), including any stereochemically isomeric form thereof, with A=(a-1) or A=(a-2) and specified values for R1, R2, R3, R4, R5, R6 and Z.
Specific substituent embodiments on the Formula (I) scaffold
Allowed embodiments include R1=chloro, Z as carbon or nitrogen in defined alternatives, and selections for R4 such as pentafluorosulfanyl, trifluoromethyl, trifluoromethoxy, or trifluoromethylthio, together with listed options for R2, R3, R5 and R6 including hydrogen, fluoro, methoxy, methyl, deuterium, or absence.
Pharmaceutically acceptable salts, solvates, or polymorphs
The Formula (I) compound is further covered as a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Optical and stereochemical embodiments
The disclosure includes stereochemically defined forms, including enantiomers and optical rotation embodiments, as part of the claimed compound family.
Overall, the claims are directed to Formula (I) substituted indoline derivatives with explicitly defined substituent alternatives, including fluorinated, sulfur-containing, and deuterated variants, and with coverage of stereochemically isomeric forms and pharmaceutically acceptable salts, solvates, and polymorphs.
Stated Advantages
Potent antiviral activity against all four DENV serotypes.
Use as dengue viral replication inhibitors.
Intended for preventing and/or treating dengue infections.
Documented Applications
Medicaments and pharmaceutical compositions for use in preventing and/or treating dengue infections.
Dengue viral replication inhibition.
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