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 • Fortin, Jérôme Michel Claude • Mercey, Guillaume Jean Maurice • Raboisson, Pierre Jean-Marie Bernard

Assignees

CISTIM LEUVEN VZW • Katholieke Universiteit Leuven • Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Pharmaceuticals Inc

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 a compound of formula (I), including any stereochemically isomeric form thereof, and pharmaceutically acceptable salt, solvate, or polymorph. The compound is defined by specific allowable substituent selections for R1, R2, and R3, together with a substituent group A defined by particular structural connectivities linking X and Y.

R1 is trifluoromethyl, trifluoromethoxy, or chloro; R2 is hydrogen, fluoro, or methoxy; and R3 is hydrogen or methoxy. Group A is —(CH2)n— where n is 3 or 4, —O—(CH2)n— where n is 2 or 4, —CH2—O—(CH2)n— where n is 2, or —X—Y— where X is —O—, —OCH2—, or —NH— and Y is C3-4 cycloalkyl optionally substituted with fluoro, or bicyclo[1.1.1]pentanyl.

The described materials include stereochemically defined compound embodiments and specific stereoisomeric forms, including enantiomers and stereoisomers designated in the examples. Characterization is reported with 1H NMR, LC/MS, optical rotation in DMF, chiral SFC purity, and related stereochemical labeling, supporting identification of the disclosed forms.

Claims Coverage

The independent claim covers a stereochemically isomeric compound of formula (I) with defined substituent choices for R1, R2, and R3 and a defined substituent group A including multiple structural connectivities. The claim also covers pharmaceutically acceptable salts, solvates, and polymorphs. Five main inventive features are consistently present: the formula (I) scaffold, the defined A connectivity, the restricted Y motif, pharmaceutically acceptable forms, and stereochemical coverage.

Overall, the claims are directed to a stereochemically defined compound of formula (I) with specified R1/R2/R3 substituent options and a defined A group connecting X and Y to yield a C3-4 cycloalkyl or bicyclo[1.1.1]pentanyl motif. Coverage extends to pharmaceutically acceptable salts, solvates, polymorphs, stereochemically isomeric forms, and use for inhibiting Dengue virus replication.

Stated Advantages

Documented Applications