TG2 inhibitor piperazine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10894777-B2
Application number	US-201716093751-A
Country	US
Kind code	B2
Filing date	Apr 13, 2017
Priority date	Apr 15, 2016
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

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:

First claim

What is claimed is:

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.

Assignees

• Univ Ottawa
• Univ Maryland
• Univ Rochester

Inventors

• Keillor Jeffrey W
• Akbar Abdullah
• Eckert Richard L
• Fisher Matthew
• Johnson Gail V W

Classifications

• C07D295/192

  from aromatic carboxylic acids · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07C317/36

  with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms · CPC title

• C07D241/04 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title