Identification of novel benzothiazones as tau-sh3 interaction inhibitors for the treatment of alzheimer’s disease

A compound having a structure represented by a formula:

• wherein each of n and m is independently 0, 1, or 2;
• wherein Q is selected from the group consisting of —O—, —S—, and —CH2—;
• wherein Z is selected from the group consisting of —C(O)—, —CH(OH)—, and —CH2—;
• wherein L is selected from the group consisting of —C(O)— and —CH2—;
• wherein each of R1 and R3 is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
• wherein each of R2a, R2b, R2c, and R2d is independently selected from the group consisting of hydrogen, halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R20, —CO2R21, —C(O)NR22, and —SO2R23;
• wherein each occurrence of R20, R21, R22, and R23, when present, is independently selected from the group consisting of hydrogen and C1-C4 allyl;
• and
• wherein each occurrence of R4a and R4b, when present, is independently selected from hydrogen, C1-C4 allyl, and C1-C4 haloalkyl;
• wherein Ar1 is selected from the group consisting of aryl and heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from the group consisting of hydrogen, halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R24, —CO2R25, —C(O)NR26, and —SO2R27;
• and
• wherein each occurrence of R24, R25, R26, and R27, when present, is independently selected from the group consisting of hydrogen and C1-C4 allyl,
• provided that when Q is —O— then Z is —CH(OH)— or —CH2—, and
• provided that when Q is —O— Z is —CH2—, then each of R2a, R2b, R2c, and R2d is hydrogen, and Ar1 is 2-pyridinyl, and
• provided that when Q is —CH2 then Z is —C(O)—, and
• provided that when n is 1 or 2, m is 1, L is —C(O)—, Q is —S—, and Ar1 is 2-pyridinyl, then Z is —CH2—,
• or a pharmaceutically acceptable salt thereof.