Compositions and Methods for Inhibiting an Isoform of Human Manganese Superoxide Dismutase

Abstract

The present invention is directed to methods of modulating the activity of an isoform of manganese superoxide dismutase which is useful for the treatment of diseases such as neurodegenerative diseases and heart failure.

1 . A method of treating a neurodegenerative disease in an individual comprising administering to said individual a therapeutically effective amount of a compound of Formula I:
   Alk-L 1 -L 2 -D  I
   or pharmaceutically acceptable salt or prodrug thereof, wherein:   Alk is C 2-100  alkenyl or C 2-100  alkynyl, each optionally substituted by one or more R 1 ;   L 1  is O, S, CO, C(O)O, C(O)NR 2 , SO, S(O) 2 , S(O)NR 2 , S(O) 2 NR 2 , NR 2 , NR 2 C(O)NR 3 , or NR 2 C(S)NR 3 ;   L 2  is absent, C 1-6  alkylenyl, C 2-6  alkenylenyl, or C 2-6  alkynylenyl, each optionally substituted by one or more R 4 ;   D is aryl or heteroaryl, each optionally substituted by one or more R 5 ;   R 1  and R 4  are each, independently, halo, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, C 3-7  cycloalkyl, heterocycloalkyl, S(O)R 6 , S(O) 2 R 6 , C(O)R 6 , OR 7 , SR 7 , C(O)OR 7 , NR 8 R 9  or NR 8 C(O)R 6 ;   R 2  and R 3  are each, independently, H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, aryl, heteroaryl, C 3-7  cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;   (C 3-7  cycloalkyl)alkyl or heterocycloalkylalkyl;   R 5  is halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-4  haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR 12 , SR 12 , C(O)R 13 , C(O)NR 14 R 15 , C(O)OR 12 , OC(O)R 13 , OC(O)NR 14 R 15 , NR 14 R 15 , NR 14 C(O)R 15 , NR 14 C(O)OR 12 , S(O)R 13 , S(O)NR 14 R 15 , S(O) 2 R 13 , or S(O) 2 NR 14 R 15 ;   R 6  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, aryl, heteroaryl, C 3-7  cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3-7  cycloalkyl)alkyl, heterocycloalkylalkyl, or NR 10 R 11 ;   R 7  is H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C 3 -C 7  cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C 3-7  cycloalkyl)alkyl or heterocycloalkylalkyl;   R 8  and R 9  are each, independently, H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, aryl, heteroaryl, C 3-7  cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;   (C 3-7  cycloalkyl)alkyl or heterocycloalkylalkyl;   or R 8  and R 9  together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;   R 10  and R 11  are each, independently, H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, C 3 -C 7  cycloalkyl or heterocycloalkyl;   R 12  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;   R 13  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; and   R 14  and R 15  are each, independently, H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or   R 14  and R 15  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.   
     
     
         2 - 47 . (canceled)