Small molecules as epigenetic modulators of lysine-specific demethylase 1 and methods of treating disorders
The invention provides for novel compounds which are inhibitors of lysine-specific demethylase 1 (LSD1) such as those according to Formula II. Such compounds may be used to treat disorders, including cancer.
1. A compound of formula II,
wherein
Y is
J is O;
R 3 is nitro, hydroxy, thio, C(O)NR A R B , or C(O)NH 2 ;
R 4 is H, alkyl, aryl, carbocyclic, heterocyclic, aralkyl, alkoxy, aryloxy, haloalkyl, or halo, each of which is optionally substituted, nitro, hydroxy, thio, C(O)NR A R B , or C(O)OR A ;
R 5 is H, alkyl, aryl, carbocyclic, heterocyclic, aralkyl, alkoxy, aryloxy, haloalkyl, or halo, each of which is optionally substituted, nitro, hydroxy, thio, C(O)NR A R B , or C(O)OR A ;
wherein R 3 is ortho substituted;
each R 1D or R 1E , is independently H, alkyl, aryl, carbocyclic, heterocyclic, alkoxy, or halo, each of which is optionally substituted;
R A and R B are each independently selected at each occurrence from the following: optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen; and
q is 1, 2, 3, 4, 5, 6, or 7.
2. The compound of claim 1 , wherein q is 1.
3. The compound of claim 1 , wherein R 3 is nitro, hydroxy, thio, or C(O)NH 2 .
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with a pharmaceutically acceptable carrier or excipient.
5. A kit comprising an effective amount of a compound of claim 1 in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to a LSD1-related disease.
6. The compound of claim 1 , of formula II-A,
wherein
R 3 is nitro, hydroxy, thio, C(O)NR A R B , or C(O)NH 2 ;
R 4 is H, alkyl, aryl, carbocyclic, heterocyclic, aralkyl, alkoxy, aryloxy, haloalkyl, or halo, each of which is optionally substituted, nitro, hydroxy, thio, C(O)NR A R B , or C(O)OR A ;
R 5 is H, alkyl, aryl, carbocyclic, heterocyclic, aralkyl, alkoxy, aryloxy, haloalkyl, or halo, each of which is optionally substituted, nitro, hydroxy, thio, C(O)NR A R B , or C(O)OR A ; and
R A and R B are each independently selected at each occurrence from the following: optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen.
7. The compound of claim 1 , selected from the following: