TG2 inhibitor piperazine compounds and uses thereof
There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided:
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —C(O)—R a ;
R 2 is H or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C(O)NH 2 , C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , OH, and OC(O)NH 2 ;
R 3 is —C(O)—Re or —S(O) 2 —R b ;
R a is —CH 2 CH 2 -phenyl, —OCH 2 -phenyl, —OCH 2 -naphthalen-2-yl, —OCH 2 -pyridin-3-yl, —OCH 2 -quinolin-3-yl, phenyl, naphthalen-2-yl, or pyridin-3-yl;
R b is phenyl, naphthalen-1-yl, 5-(dimethylamino)naphthalen-1-yl, naphthalen-2-yl, 7-hydroxy-2H-chromen-2-on-3-yl, or 7-methoxy-2H-chromen-2-on-3-yl; and
n is 1, 2, 3, or 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(O)OCH 2 -phenyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H or CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 4.
5. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. A method for inhibiting tissue transglutaminase 2 activity in a cell, comprising contacting the cell with the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 , wherein the inhibition is of a tissue transglutaminase 2 activity selected from the group consisting of guanosine triphosphatase activity, guanosine triphosphate binding activity, and transamidation activity of transglutaminase 2, or a combination thereof.
10. The method of claim 8 , wherein contacting the cell with the compound holds tissue transglutaminase 2 in an open conformation.
11. A method for inhibiting tissue transglutaminase 2 activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 , wherein the inhibition is of a tissue transglutaminase 2 activity selected from the group consisting of guanosine triphosphatase activity, guanosine triphosphate binding activity, and transamidation activity of transglutaminase 2, or a combination thereof.