Inhibitors of PARPs that catalyze mono-ADP-ribosylation

Patent metadata

Field	Value
Publication number	US-10899733-B2
Application number	US-201816109643-A
Country	US
Kind code	B2
Filing date	Aug 22, 2018
Priority date	Aug 23, 2017
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

Provided herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof:

which are useful as PARP inhibitors, as well as pharmaceutical compositions comprising them and methods for their use in treating disorders.

First claim

What is claimed:

1. A compound of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is selected from the group of —(CH 2 ) n 1 -phenyl, —(CH 2 ) n 2 -naphthalenyl, and —(CH 2 ) n 3 -Het, wherein Het is a 5- to 10-membered heterocyclic group having 1, 2, 3, or 4 ring nitrogen atoms; with each of the R 1 phenyl, naphthalenyl, and Het rings of the —(CH 2 ) n 1 -phenyl, —(CH 2 ) n 2 -naphthalenyl, and —(CH 2 ) n 3 -Het groups, respectively, being independently substituted by 0, 1, 2, 3, 4, or 5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, halogen, CF 3 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, —CO 2 -benzyl, —CO 2 —C 3 -C 6 cycloalkyl, and —CO 2 —CH 2 —C 3 -C 6 cycloalkyl; and
n 1 , n 2 , and n 3 are integers independently selected in each instance from 0, 1, 2, and 3.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group of phenyl, naphthalenyl, and Het, wherein Het is a 5- to 10-membered heterocyclic group having 1, 2, 3, or 4 ring nitrogen atoms; with each of the R 1 phenyl, naphthalenyl, and Het rings being independently substituted by 0, 1, 2, 3, 4, or 5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, halogen, CF 3 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, —CO 2 -benzyl, —CO 2 —C 3 -C 6 cycloalkyl, and —CO 2 —CH 2 —C 3 -C 6 cycloalkyl.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group of phenyl, naphthalenyl, benzyl, pyridinyl, pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, piperazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl, purinyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrrolo[2,3-b]pyridinyl; with each of the R 1 rings being independently substituted by 0, 1, 2, 3, 4, or 5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, halogen, CF 3 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, —CO 2 -benzyl, —CO 2 —C 3 -C 6 cycloalkyl, and —CO 2 —CH 2 —C 3 -C 6 cycloalkyl.

4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group of phenyl, naphthalenyl, benzyl, quinolinyl, indolyl, pyridinyl, pyrrolo[2,3-b]pyridinyl; with each of the R 1 rings being independently substituted by 0, 1, 2, 3, 4, or 5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, halogen, CF 3 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, —CO 2 -benzyl, —CO 2 —C 3 -C 6 cycloalkyl, and —CO 2 —CH 2 —C 3 -C 6 cycloalkyl.

5. The compound of claim 2 of Formula VI, or a pharmaceutically acceptable salt thereof:

wherein:
R 7 is selected from the group of H, F, CI, CH 3 , CF 3 , CO 2 H, and —CO 2 (C 1 -C 6 alkyl);
X 1 is selected from the group of CH and N; and
X 2 is selected from the group of CH and N;

with the proviso that only one of X 1 and X 2 can be N; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 2 selected from the group of:

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 2 , a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 7 , wherein the compound of claim 2 is selected from the group of:

9. The compound of claim 5 , wherein X 1 is N and X 2 is CH, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 5 , wherein X is CH and X 2 is N, or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Oregon Health & Science

Inventors

• Cohen Michael
• Morgan Rory

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D217/24

  Oxygen atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title