Thieno[3,2-c]pyridine potassium channel inhibitors

摘要

The present invention provides thienopyridine compounds which are potassium channel inhibitors. In another embodiment, the invention provides pharmaceutical compositions comprising thienopyridines. In another embodiment, the invention provides methods of using thienopyridines in the treatment or prevention of cancer, arrhythmias, autoimmune diseases and inflammatory diseases, including gastric cancer, atrial fibrillation, type-2 diabetes mellitus, rheumatoid arthritis, type-1 diabetes, inflammatory bowel disorder and demyelinating disorders such as multiple sclerosis.

主权项

1. A compound of the formula: wherein: R1 is unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10, and hydroxyl; or unsubstituted or substituted heteroaryl, wherein the substituents are selected from the group consisting of cyano, nitro, halogen, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10 and hydroxyl; R2 is H or unsubstituted or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, cyano, nitro, NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, aryloxy, heteroaryloxy, CO2R7, C(O)NR9R10, NHC(O)R7 and SO2NR9R10; R3 is unsubstituted or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, cyano, nitro, NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, aryloxy, heteroaryloxy, CO2R7, C(O)NR9R10, NHC(O)R7 and SO2NR9R10; unsubstituted alkoxy; unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10, and hydroxyl; or NR5R6; R4 is H; unsubstituted or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, cyano, nitro, NR9R10, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, aryloxy, heteroaryloxy, CO2R7, C(O)NR9R10, NHC(O)R7 and SO2NR9R10; unsubstituted alkoxy; unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10, and hydroxyl; or NR5R6; R5 and R6 may be the same or different, and may be H; unsubstituted or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, cyano, nitro, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, aryloxy, and heteroaryloxy; unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10, and hydroxyl; unsubstituted or substituted heteroaryl, wherein the substituents are selected from the group consisting of cyano, nitro, halogen, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10 and hydroxyl; or unsubstituted cycloalkyl; or R5 and R6 may together form a saturated or partially saturated 4 to 7 membered ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; R7 is H; unsubstituted or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, cyano, nitro, alkoxy, hydroxyl, unsubstituted aryl, unsubstituted heteroaryl, aryloxy, and heteroaryloxy; unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, and alkoxy; unsubstituted or substituted heteroaryl, wherein the substituents are selected from the group consisting of cyano, nitro, halogen, unsubstituted alkyl, alkylthio, and alkoxy; or unsubstituted cycloalkyl; X is NR8; R8 is H; L is (CH2)n, where n is 0, 1, 2, 3 or 4; Y is unsubstituted or substituted aryl, wherein the substituents are selected from the group consisting of cyano, halogen, nitro, trifluoromethyl, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10, and hydroxyl; or unsubstituted or substituted heteroaryl, wherein the substituents are selected from the group consisting of cyano, nitro, halogen, unsubstituted alkyl, alkylthio, alkoxy, NR9R10, CO2R7, C(O)NR9R10, NHC(O)R7, SO2NR9R10 and hydroxyl; and R9 and R10 can be the same or different, and may be H, unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, hydroxyethyl, or alkoxyethyl, or R9 and R10 may together form a saturated or partially saturated 4 to 7 membered ring; or the products of oxidation of sulphur and/or nitrogen moieties on these molecules, or a pharmaceutically acceptable salt thereof.