3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase

摘要

The present invention relates to 3-hydroxypyrrolidine compounds of the general formula (I) which are inhibitors of 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase. The invention also relates to the use of these compounds in the treatment of diseases or conditions in which it is desirable to inhibit 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase including cancer, and to pharmaceutical compositions containing the compounds.

主权项

1. A compound of the formula (I): where: X is a cycloalkyl, alkenyl, alkynyl or aryl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR2R3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; or X is a butyl, isobutyl, or pent-3-yl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR2R3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; or X is an alkyl group which is substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole, or NR2R3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; or X is SR1; or X is NR2R3; or X is propyl; R1, R2 and R3 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR2aR3a group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; R2a and R3a are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano or thiazole group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups; A is CH; B is NH2 or NHR5; R5 is an alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, or aryl group, each of which is optionally substituted with one or more halogen or hydroxy groups; and D is H, OH, NH2, or SCH3; or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof; provided that when B is NH2, and D is H, X is not propyl, CH2OH, CH2SQ, where Q is an optionally substituted alkyl or aryl group, or CH2OQ, where Q is an optionally substituted alkyl group.