Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as PARP inhibitors
Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.
1. A compound of Formula (I):
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 ;
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 10 , —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.
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, 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 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 —, and said ring is optionally substituted with at least one substituent R 12 , provided that
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 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— or —SO 2 —; 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 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 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 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 —, and said ring is optionally substituted with at least one substituent R 12 ,
provided that
when one of R 3 and R 4 is oxo, the other is absent, and
when one of R 7 and R 8 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— or —SO 2 —; and
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.
4. A compound selected from the group consisting of:
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
5. 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 , or a stereoisomer or a pharmaceutically acceptable salt thereof.
6. A compound having the following formula
or a stereoisomer or a pharmaceutically acceptable salt thereof.