Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors

Patent metadata

Field	Value
Publication number	US-9617273-B2
Application number	US-201614988484-A
Country	US
Kind code	B2
Filing date	Jan 5, 2016
Priority date	Dec 31, 2011
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
R N is hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C 1 -C 12 alkoxyl;
X is C or N;
m and n are each 1 or 2;
t is 0 or 1;
R 1 at each occurrence, is independently selected from halogen, CN, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 2 is hydrogen or alkyl;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 , which may be the same or different, are each independently selected from hydrogen, —OR 9 , —COR 9 , —CO 2 R 9 , alkyl, cycloalkyl, or aryl,
or (R 3 and R 4 ), and/or (R 4 and R 5 ), and/or (R 5 and R 6 ), and/or (R 6 and R 7 ), and/or (R 7 and R 8 ), together with the atom(s) they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR 13 —, —O—, —S—, —SO— or —SO 2 —;
provided that when X is N, R 6 is absent,
R 9 and R 10 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl,
wherein the cycloalkyl is a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic, bicyclic and tricyclic groups, and comprising from 3 to 12 carbon atoms;
wherein the heteroaryl is a group selected from:
5- to 7-membered aromatic, monocyclic rings comprising at least one heteroatom selected from N, O, and S, with the remaining ring atoms being carbon;
8- to 12-membered bicyclic rings comprising at least one heteroatom selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
11- to 14-membered tricyclic rings comprising at least one heteroatom selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and

wherein the heterocyclyl is a ring selected from 4- to 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, comprising at least one carbon atoms in addition to at least one heteroatom selected from oxygen, sulfur, and nitrogen.

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

or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
R N is selected from hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C 1 -C 12 alkoxyl;
m and n are each 1 or 2;
t is 0 or 1;
R 1 , at each occurrence, is independently selected from halogen, CN, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R 12 ;
R 2 is selected from hydrogen, COR 9 , CONR 9 R 10 , CO 2 R 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 3 , R 4 , R 5 , R 6 , R 7 and R 8 , which may be the same or different, are each independently selected from hydrogen, —OR 9 , —COR 9 , —CO 2 R 9 , alkyl, cycloalkyl, or aryl,
or (R 3 and R 4 ), and/or (R 4 and R 5 ), and/or (R 5 and R 6 ), and/or (R 6 and R 7 ), and/or (R 7 and R 8 ), together with the atom(s) to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR 13 —, —O—, —S—, —SO— and —SO 2 —;
R 9 and R 13 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

3. The compound according to claim 1 , which is a compound of Formula (III):

or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
R N is hydrogen or alkyl, wherein the alkyl is optionally substituted with at least one of hydroxyl or C 1 -C 12 alkoxyl;
X is C or N;
m and n are each 1 or 2;
t is 0 or 1;
R 1 , at each occurrence, is independently selected from halogen, CN, NO 2 , OR 9 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R 10 , CONR 9 R 10 , COOR 9 , SO 2 R 9 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 2 is hydrogen or alkyl;
R 3 , R 4 , R 5 , R 7 and R 8 , which may be the same or different, are each independently selected from hydrogen, —OR 9 , —COR 9 , —CO 2 R 9 , alkyl, cycloalkyl, or aryl,
or (R 3 and R 4 ), and/or (R 4 and R 5 ), and/or (R 5 and R 7 ), and/or (R 7 and R 8 ), together with the atom(s) they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 heteroatoms independently selected from —NR 13 —, —O—, —S—, —SO—, and —SO 2 —;
R 9 and R 10 , which may be the same or different, are each selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

4. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of the compound of claim 1 .

5. The compound of claim 3 , wherein t is 1.

6. The compound of claim 3 , wherein R 1 is halogen or alkyl.

7. The compound of claim 6 , wherein R 1 is F.

8. The compound of claim 3 , wherein R 4 and R 5 together with the atoms to which they are attached, form a 5-membered saturated ring having one nitrogen.

9. The compound of claim 3 , wherein R N is hydrogen.

10. The compound of claim 3 , wherein R 3 is hydrogen.

Assignees

• Beigene Ltd

Inventors

• Zhou Changyou
• Ren Bo
• Wang Hexiang

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D487/06 Primary

  Peri-condensed systems · CPC title