PARG inhibitors and method of use thereof

Patent metadata

Field	Value
Publication number	US-11858879-B2
Application number	US-201816625511-A
Country	US
Kind code	B2
Filing date	Jun 22, 2018
Priority date	Jun 23, 2017
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

Provided herein are, inter alia, compounds inhibiting poly(ADP-ribose) Glycohydrolase (PARG) in a cancer cell and methods of treating cancer using compounds of the invention.

First claim

What is claimed is:

1. A compound of formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:
R 1D is hydrogen or —CH 3 ;
R 6 is hydrogen or —C(O)—OR 6C ;
R 7 is hydrogen or halogen; and
R 8 is —OR 8D , —C(O)—OR 8C , or unsubstituted C 2 -C 4 alkyl; and
R 6C , R 8C and R 8D are independently hydrogen or —CH 3 .

2. A compound of formula (IX),

or a pharmaceutically acceptable salt thereof, wherein:
R 1D , R 2D , and R 3D are independently hydrogen or unsubstituted C 1 -C 4 alkyl; and
R 6 is hydrogen, halogen, —C(O)—OR 6C , —OR 6D , or unsubstituted C 1 -C 4 alkyl; and
R 6C and R 6D are independently hydrogen or —CH 3 .

3. The compound of claim 2 , wherein:
R 1D , R 2D , and R 3D are independently hydrogen or —CH 3 .

4. The compound of claim 1 , wherein the compound is:

5. A method of treating cancer in a subject suffering therefrom, the method comprising administering to the subject an effective amount of a compound having formula (VIII),

or a pharmaceutically acceptable salt thereof,
wherein:
R 1D is hydrogen or —CH 3 ;
R 6 is hydrogen or —C(O)—OR 6C ;
R 7 is hydrogen or halogen; and
R 8 is —OR 8D , —C(O)—OR 8C , or unsubstituted C 2 -C 4 alkyl; and
R 6C , R 8C , and R 8D are independently hydrogen or —CH 3 ;
wherein the cancer is selected from: breast cancer, ovarian cancer, lung cancer, pancreatic cancer, glioblastoma, uterine cancer, bladder cancer, esophagus cancer, gastric cancer, head and neck cancer, cholangiocarcinoma, mesothelioma, prostate cancer, colon carcinoma, fallopian tube cancer, lymphoma and leukemia.

6. A method of treating cancer in a subject suffering therefrom, the method comprising administering to the subject an effective amount of a compound having formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:
R 1D , R 2D , and R 3D are independently hydrogen or unsubstituted C 1 -C 4 alkyl;
R 6 is hydrogen, halogen, —C(O)—OR 6C , —OR 6D , or unsubstituted C 1 -C 4 alkyl, and
R 6C and R 6D are independently hydrogen or —CH 3 ;
wherein the cancer is selected from: breast cancer, ovarian cancer, lung cancer, pancreatic cancer, glioblastoma, uterine cancer, bladder cancer, esophagus cancer, gastric cancer, head and neck cancer, cholangiocarcinoma, mesothelioma, prostate cancer, colon carcinoma, fallopian tube cancer, lymphoma and leukemia.

7. The method of claim 6 , wherein:
R 1D , R 2D , and R 3D are independently hydrogen or —CH 3 .

8. The method of claim 5 , wherein the compound is:

9. The method of claim 5 , wherein the compound inhibits poly(ADP-ribose) glycohydrolase (PARG) in a cancer cell;
wherein the cancer is selected from: breast cancer, ovarian cancer, lung cancer, pancreatic cancer, glioblastoma, uterine cancer, bladder cancer, esophagus cancer, gastric cancer, head and neck cancer, cholangiocarcinoma, mesothelioma, prostate cancer, colon carcinoma, fallopian tube cancer, lymphoma and leukemia.

10. A method of inhibiting a poly(ADP-ribose) glycohydrolase (PARG), the method comprising contacting the PARG with a compound having a formula (VIII) or (IX):

or a pharmaceutically acceptable salt thereof, wherein:
R 1D is hydrogen or —CH 3 ;
R 6 is hydrogen or —C(O)—OR 6C ;
R 7 is hydrogen or halogen;
R 8 is —OR 8D , —C(O)—OR 8C , or unsubstituted C 2 -C 4 alkyl;
R 6C , R 8C , and R 8D are independently hydrogen or —CH 3 ; and
R 2D , and R 3D are independently hydrogen or unsubstituted C 1 -C 4 alkyl.

11. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (VIII) or (IX),

or a pharmaceutically acceptable salt thereof, wherein:
R 1D is hydrogen or —CH 3 ;
R 6 is hydrogen or —C(O)—OR 6C ;
R 7 is hydrogen or halogen;
R 8 is —OR 8D , —C(O)—OR 8C , or unsubstituted C 2 -C 4 alkyl;
R 6C , R 8C , and R 8D are independently hydrogen or —CH 3 ; and
R 2D , and R 3D are independently hydrogen or unsubstituted C 1 -C 4 alkyl.

Assignees

• Hope City

Inventors

• Yu Xiaochun
• Chen Shih-Hsun
• Yuan Yate-Ching
• Li Hongzhi
• Horne David

Classifications

• C07C251/86 Primary

  having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C311/17

  to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• C07C311/29

  having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C323/42 Primary

  Y being a carbon atom of a six-membered aromatic ring · CPC title