Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors

Patent metadata

Field	Value
Publication number	US-10112952-B2
Application number	US-201715479958-A
Country	US
Kind code	B2
Filing date	Apr 5, 2017
Priority date	Dec 31, 2011
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

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 method of treating a disease responsive to inhibition of PARP comprising administering to a subject in need thereof a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit said PARP:

wherein:
R N is selected from hydrogen, 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 ;
X is selected from the group consisting of C, N, O, and S;
m and n, which may be the same or different, are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
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, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R 12 ;
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, halogen, —NR 9 R 10 , —OR 9 , oxo, —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —NR 9 CONR 10 R 11 , —NR 9 CO 2 R 10 , —NR 9 SO 2 R 10 , —SO 2 R 9 , alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is independently optionally substituted with at least one substituent R 12 ,
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 —, and said ring is optionally substituted with at least one substituent R 12 ,
provided that
when X is O, R 5 and R 6 are absent,
when X is N, R 6 is absent,
when X is S, R 5 and R 6 are absent, or at least one of R 5 and R 6 is oxo,
when one of R 3 and R 4 is oxo, the other is absent,
when one of R 7 and R 8 is oxo, the other is absent, and
when X is C and one of R 5 and R 6 is oxo, the other is absent;

R 9 , R 10 , and R 11 , 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, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R 12 ;
R 12 is selected from CN, halogen, haloalkyl, NO 2 , —NR′R″, —OR′, oxo, —COR′, —CO 2 R′, —CONR′R″, —NR′CONR″R′″, —NR′CO 2 R″, —NR′SO 2 R″, —SO 2 R′, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a 3- to 8-membered saturated, partially or fully unsaturated ring having 0, 1 or 2 additional heteroatoms independently selected from —NR 13 —, —O—, —S—, —SO— and —SO 2 —; and
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,
wherein the disease is selected from ovarian cancer or breast cancer.

2. The method of claim 1 , 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.

3. The method of claim 1 , wherein X is C or N.

4. The method of claim 1 , wherein m and n are each 1 or 2.

5. The method of claim 1 , wherein t is 0 or 1.

6. The method of claim 1 , wherein R 2 is hydrogen or alkyl.

7. The method of claim 1 , wherein 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.

8. The method of claim 1 , wherein the compound is a compound of Formula (II):

or a stereoisomer or a pharmaceutically acceptable salt thereof,
wherein:
R N is selected from hydrogen, 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 ;
m and n, which may be the same or different, are each an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
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, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with at least one substituent R 12 ;
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, halogen, —NR 9 R 10 , —OR 9 , oxo, —COR 9 , —CO 2 R 9 , —CONR 9 R 10 , —NR 9 CONR 10 R 11 , —NR 9 CO 2 R 10 , —NR 9 SO 2 R 10 , —SO 2 R 9 , alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, alkynyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is independently optionally substituted with at least one substituent R 12 , 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 a

Assignees

• Beigene Ltd

Inventors

• Zhou Changyou
• Ren Bo
• Wang Hexiang

Classifications

• A61K31/551

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D471/16 Primary

  Peri-condensed systems · CPC title

• C07D471/22

  in which the condensed systems contains four or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title