Substituted cycloocta[5,6]pyrido[4,3,2-de]phthalazines as PARP inhibitors

Patent metadata

Field	Value
Publication number	US-9328111-B2
Application number	US-201114369388-A
Country	US
Kind code	B2
Filing date	Dec 31, 2011
Priority date	Dec 31, 2011
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present invention provides a compound of Formula (I):

wherein the variables Z, n, Y and p are as defined herein, and pharmaceutically acceptable salts thereof, which can inhibit the activity of poly (ADP-ribose)polymerases, and pharmaceutical compositions comprising the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
Y, at each occurrence, is independently selected from —CR 1 R 2 ;
p is 5;
Z, at each occurrence, is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —NO 2 , —OR 6 , —NR 6 R 7 , —NR 6 COR 7 , —NR 6 —NR 7 COR 8 , —NR 6 SO 2 R 7 , —CONR 6 R 7 , —COOR 6 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
n is 0, 1, 2 or 3;
R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR 6 R 7 , —OR 6 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 7 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted by at least one substituent R 9 ; and
R 9 , at each occurrence, is independently selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SR′, —SOR′, —SO 2 R′, —NR′SO 2 NR″R′″, and NR′SO 2 R″, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

2. The compound of claim 1 , which is a compound of Formula (II-1):

or a pharmaceutically acceptable salt thereof,
wherein
p is 5;
Z, is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —NO 2 , —OR 6 , —NR 6 R 7 , —NR 6 COR 7 , —NR 6 —NR 7 COR 8 , —NR 6 SO 2 R 7 , —CONR 6 R 7 , —COOR 6 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR 6 R 7 , —OR 6 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 7 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted by at least one substituent R 9 ; and
R 9 , at each occurrence, is independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SR′, —SOR′, —SO 2 R′, —NR′SO 2 NR″R′″, and NR′SO 2 R″, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

3. The compound of claim 1 , which is a compound of Formula (II-2):

or a pharmaceutically acceptable salt thereof,
wherein
p is 5;
Z is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —NO 2 , —OR 6 , —NR 6 R 7 , —NR 6 COR 7 , —NR 6 —NR 7 COR 8 , —NR 6 SO 2 R 7 , —CONR 6 R 7 , —COOR 6 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR 6 R 7 , —OR 6 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 7 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted by at least one substituent R 9 ; and
R 9 , at each occurrence, is independently selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SR′, —SOR′, —SO 2 R′, —NR′SO 2 NR″R′″, and NR′SO 2 R″, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

4. The compound of claim 1 , which is a compound of Formula (II-3):

or a pharmaceutically acceptable salt thereof,
wherein
p′ is 3;
Z is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —CN, —NO 2 , —OR 6 , —NR 6 R 7 , —NR 6 COR 7 , —NR 6 —NR 7 COR 8 , —NR 6 SO 2 R 7 , —CONR 6 R 7 , —COOR 6 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR 6 R 7 , —OR 6 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —NR 6 SO 2 R 7 , and —SO 2 R 6 , wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl is optionally substituted by at least one substituent R 9 ; and
R 9 , at each occurrence, is independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SR′, —SOR′, —SO 2 R′, —NR′SO 2 NR″R′″, and NR′SO 2 R″, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

5. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

6

Assignees

• Zhou Changyou
• Ren Bo
• Wang Hexiang
• Beigene Ltd

Inventors

• Zhou Changyou
• Ren Bo
• Wang Hexiang

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title