N-(5-((aryl or heteroaryl)methyloxy)pentyl)-substituted iminosugars as inhibitors of glucosylceramide synthase

A method of decreasing the level of glycosphingolipids in a subject having a disorder characterized by glycosphingolipid accumulation, comprising

• wherein:
• each of R19-R26 is independently selected from H, F, Me or Et;
• R27 and R28 is independently selected from the group consisting of H, F, CF3 and C1-C8 linear or branched alkyl;
• X is
• wherein
• Y1-Y5 are independently selected from the group of C and N-atoms provided that not more than two of Y1-Y5 are a N-atom, and provided that if one or two of Y1-Y5 is a N-atom, the R-group attached to that N-atom is void;
• Y6-Y9 are independently selected from the group of C-, S-, N- and O-atoms and comprise at least one of an S-, N- or O-atom, provided that Y6-Y9 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, and provided that if one of Y6-Y9 is a S- or O-atom, the R-group attached to any S-, N- and/or O-atom is void, and provided that if none of Y6-Y9 is a S- or O-atom, the R-group attached to any N-atom is selected from the group consisting of H, C1-C8 linear or branched alkyl, IV and V, and provided that O and S-atoms are not concomitantly present;
• one of R1-R9 is
• and the remaining of R1-R9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF3, C1-C8 linear or branched alkyl and C1-C8 linear or branched oxyalkyl;
• wherein
• Y10-Y14 are independently selected from the group of C- and N-atoms provided that not more than two of Y10-Y14 are a N-atom, and provided that if one or two of Y10-Y14 is a N-atom, the R-group attached to that N-atom is void;
• Y15-Y18 are independently selected from the group of C-, S-, N- and O-atoms and Y19 is selected from the group consisting of a C-atom and a N-atom, provided that Y15-Y19 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, provided that if one of Y15-Y19 is a S- or O-atom, the group attached to any S-, N and/or O-atom is void, and provided that if none of Y15-Y19 is a S- or O-atom, the group attached to any N-atom is selected from the group consisting of H or C1-C8 linear or branched alkyl, and provided that O and S-atoms are not concomitantly present;
• R10-R18 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF3, C1-C8 linear or branched alkyl or C1-C8 linear or branched oxyalkyl, and/or wherein two of R10-R18 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms of Y10-Y18;
• or a pharmaceutically acceptable salt thereof, in an amount effective to decrease the level of glycosphingolipids in the subject.

A method of inhibiting neutral glucosylceramidase (GBA2) in a subject having a disorder characterized by glycosphingolipid accumulation and over-activity of GBA2, comprising administering to the subject a GBA2-inhibiting compound of structure I or Ia:

• wherein:
• each of R19-R26 is independently selected from H, F, Me or Et;
• R27 and R28 is independently selected from the group consisting of H, F, CF3 and C1-C8 linear or branched alkyl;
• X is
• wherein
• Y1-Y5 are independently selected from the group of C and N-atoms provided that not more than two of Y1-Y5 are a N-atom, and provided that if one or two of Y1-Y5 is a N-atom, the R-group attached to that N-atom is void;
• Y6-Y9 are independently selected from the group of C-, S-, N- and O-atoms and comprise at least one of an S-, N- or O-atom, provided that Y6-Y9 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, and provided that if one of Y6-Y9 is a S- or O-atom, the R-group attached to any S-, N- and/or O-atom is void, and provided that if none of Y6-Y9 is a S- or O-atom, the R-group attached to any N-atom is selected from the group consisting of H, C1-C8 linear or branched alkyl, IV and V, and provided that 0 and S-atoms are not concomitantly present;
• one of R1-R9 is
• and the remaining of R1-R9 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF3, C1-C8 linear or branched alkyl and C1-C8 linear or branched oxyalkyl;
• wherein
• Y10-Y14 are independently selected from the group of C- and N-atoms provided that not more than two of Y10-Y14 are a N-atom, and provided that if one or two of Y10-Y14 is a N-atom, the R-group attached to that N-atom is void;
• Y15-Y18 are independently selected from the group of C-, S-, N- and O-atoms and Y19 is selected from the group consisting of a C-atom and a N-atom, provided that Y15-Y19 comprises at most one S-atom, at most one N-atom and/or at most one O-atom, provided that if one of Y15-Y19 is a S- or O-atom, the group attached to any S-, N and/or O-atom is void, and provided that if none of Y15-Y19 is a S- or O-atom, the group attached to any N-atom is selected from the group consisting of H or C1-C8 linear or branched alkyl, and provided that O and S-atoms are not concomitantly present;
• R10-R18 are independently selected from the group consisting of H, F, Cl, Br, I, CN, CF3, C1-C8 linear or branched alkyl or C1-C8 linear or branched oxyalkyl, and/or wherein two of R10-R18 form a linear or branched fused alkylene or alkylenedioxy ring on two adjacent atoms of Y10-Y18;
• or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit GBA2 in the subject.