Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment, amelioration or prevention of fibrotic disease

Inventors

FLÜCKIGER-MANGUAL, Stefanie • Bohnacker, Thomas

Assignees

Tolremo Therapeutics AG

Abstract

The present invention relates to a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof and to pharmaceutical compositions comprising a compound of formula (I), as well as to the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, in the treatment of fibrotic diseases, preferably idiopathic pulmonary fibrosis (IPF) or non-alcoholic steatohepatitis (NASH). Further aspects of the present invention include combination therapies in which a compound of formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, is used in combination with a known anti-fibrotic or anti-inflammatory agents for fibrotic diseases.

Core Innovation

The invention relates to a method of treating fibrotic disease by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cocrystal, tautomer, racemate, enantiomer, diastereomer, or mixture thereof. The compounds of formula (I) are defined by extensive structural constraints for substituents and ring systems, including selections for R1, R21, R3, R31, E, R6x, Ring A and Ring B.

R1 is selected from halogen, unsubstituted or substituted hydrocarbon groups containing 1 to 20 carbon atoms, and unsubstituted or substituted hydrocarbon groups containing 1 to 20 carbon atoms and 1 to 15 heteroatoms selected from O, N and S. R21 is selected from hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 alkyl containing one to three oxygen atoms between carbon atoms, and unsubstituted or substituted C3-6 cycloalkyl. R3 is selected from unsubstituted or substituted heterocyclyl, unsubstituted or substituted carbocyclyl, unsubstituted or substituted C1-6 alkylene-heterocyclyl, and unsubstituted or substituted C1-6 alkylene-carbocyclyl, and at least one of X1, X2 and X3 is N.

E is either absent or selected from CH2, CHRx, CRx2, NH, NRx, O, -L1-L2- and -L2-L1-, with L1 and L2 selected from CH2, CHRx, CRx2, NH, NRx and O. Ring A is further unsubstituted or substituted with one or more groups Rx, where any two Rx groups can be separate substituents or linked with each other, or Ring A can be substituted to form a bicyclic moiety with a partial structure. Ring B is an unsubstituted or substituted heterocycle or unsubstituted or substituted carbocycle.

The disclosure further describes specific compound examples within the scaffold, including analogs bearing oxadiazole- and triazole-substituted substituents, and reports preparation and characterization examples, a crystal-structure determination workflow for CREBBP bromodomain bound to compound 00004, and associated potency and affinity characterization. Functional results are reported for compound 00004 in vitro, including reduction of fibrotic gene expression and inhibition of TGF-β1–induced αSMA and FN1 in IPF donor cells.

Claims Coverage

The partial content includes one independent claim directed to a method of treating fibrotic disease. It covers administration of a therapeutically effective amount of a compound of formula (I) or specified pharmaceutical forms, with the chemical scope controlled by extensive structural limitations across multiple substituent and ring variables.

The claim coverage centers on a fibrotic-disease treatment method using formula (I) compounds, with the inventive scope defined by constrained substituent selections, the requirement that at least one of X1, X2 and X3 is N, the E linker framework, and the Ring A/Ring B structural options.

Stated Advantages

Documented Applications