Tricyclic compounds for inhibiting the CFTR channel

摘要

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.;

主权项

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: wherein R1 represents phenyl, (C4-C7)cycloalkenyl or Het1, which R1 group may be unsubstituted or substituted on one or two carbon atoms by substituents Ra, and may further be substituted on a nitrogen atom with a substituent Ra1; each Ra independently represents (C1-C4)alkyl, halo, halo(C1-C4)alkyl, cyano, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, R6OC(O)—, or R6OC(O)(C1-C4)alkyl-; Ra1 represents (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl-, di[(C1-C4)alkyl]amino(C1-C4)alkyl-, aryl(C1-C4)alkyl or R6OC(O)(C1-C4)alkyl-; R2 represents (C1-C6)alkyl, (C3-C7)cycloalkyl, (C4-C7)cycloalkenyl, phenyl, furanyl, thiazolyl or thienyl, which R2 may be unsubstituted or substituted on from one to three carbon atoms with substituents Rb; each Rb independently represents (C1-C4)alkyl, halo, halo(C1-C4)alkyl, cyano, (C1-C4)alkylamino(C1-C4)alkyl-, di[(C1-C4)alkyl]amino(C1-C4)alkyl-, (R6)2NC(O)(C1-C4)alkyl- or R6OC(O)(C1-C4)alkyl-; X represents S, Z represents CHR4a and n represents 1; or X represents CHR4b, Z represents NR5 and n represents 1 or 2; or X represents CHR4b, Z represents CHR4a and n represents 0, 1 or 2; or X represents C(═CH2), CF2 or C(CH3)2, Z represents CHR4a and n represents 0 or 1; each R3 independently represents methyl or ethyl; when X represents S, R4 represents hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl-, amino(C1-C4)alkyl-, (C1-C4)alkylamino(C1-C4)alkyl-, di[(C1-C4)alkyl]amino(C1-C4)alkyl-, phenyl, Het1(C1-C4)alkyl-, Het2(C1-C4)alkyl-, (C1-C4)alkylS(O)2NH(C1-C4)alkyl-, or R7C(O)NH(C1-C4)alkyl-; when X represents CHR4b, each R4 independently represents hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl-, amino(C1-C4)alkyl-, (C1-C4)alkylamino(C1-C4)alkyl-, di[(C1-C4)alkyl]amino(C1-C4)alkyl-, amino, (C1-C4)alkylamino-, di[(C1-C4)alkyl]amino-, phenyl, Het1(C1-C4)alkyl-, Het2(C1-C4)alkyl-, (C1-C4)alkylS(O)2NH(C1-C4)alkyl-, or R7C(O)NH(C1-C4)alkyl-; R4a represents hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkyl, amino(C1-C4)alkyl-, (C1-C4)alkylamino(C1-C4)alkyl-, di[(C1-C4)alkyl]amino(C1-C4)alkyl-, Het1(C1-C4)alkyl-, Het2(C1-C4)alkyl-, or R6OC(O)—; R4b represents hydrogen or methyl; R5 represents hydrogen or (C1-C4)alkyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents (C1-C2)alkyl, (C1-C2)alkoxy, (C1-C2)alkoxy(C1-C2)alkyl or phenyl; Het1 represents a 5- or 6-membered heteroaryl ring comprising a) one oxygen or sulphur atom and optionally one or two nitrogen atoms; or b) from one to four nitrogen atoms; and Het2 represents a 4- to 7-membered heterocyclic ring comprising a) 1 or 2 heteroatoms selected from N, O and S; or b) —C(O)— and 1 or 2 heteroatoms selected from N and O.