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. An oral dosage form comprising a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit PARP:
wherein:
R N is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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 C, N, O, or 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, or 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, or 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, or 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, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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, or heterocyclyl,
wherein the cycloalkyl is a hydrocarbon group selected from saturated or partially unsaturated cyclic hydrocarbon groups, comprising monocyclic, bicyclic or 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, or S, with the remaining ring atoms being carbon;
8- to 12-membered bicyclic rings comprising at least one heteroatom selected from N, O, or 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, or 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 or tricyclic, saturated or partially unsaturated rings, comprising at least one carbon atoms in addition to at least one heteroatom selected from oxygen, sulfur, or nitrogen;
and a pharmaceutically acceptable carrier.
2. The oral dosage form 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 oral dosage form of claim 1 , wherein X is C or N.
4. The oral dosage form of claim 1 , wherein m and n are each 1 or 2.
5. The oral dosage form of claim 1 , wherein t is 0 or 1.
6. The oral dosage form of claim 1 , wherein R 2 is hydrogen or alkyl.
7. The oral dosage form 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 oral dosage form 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, or 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, or 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, or 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, or 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— or —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, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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, or heterocyclyl.
9. The oral dosage form of claim 8 , 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, or 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, or 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— or —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, or heteroaryl; and
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
10. The oral dosage form of claim 1 , wherein the compound 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, or 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, or 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, or 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, or heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or 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—, or —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, or 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, or heteroaryl, wherein R′, R″, and R′″ are independently selected from hydrogen, haloalkyl, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 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, or heterocyclyl.
11. The oral dosage form of claim 10 , 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, or 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—, or —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, or heteroaryl; and
R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
12. The oral dosage form of claim 1 , wherein the compound is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
13. The oral dosage form of claim 1 , wherein the compound is selected from the group consisting of:
or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
14. The oral dosage form of claim 1 , wherein the dosage form is a tablet or a capsule.
15. The oral dosage form of claim 1 , wherein the compound is
or a stereoisomer or a pharmaceutically acceptable salt thereof.
16. The oral dosage form of claim 14 , wherein the dosage form comprises about 10 mg to about 500 mg of the compound.
17. The oral dosage form of claim 15 , wherein the dosage form comprises about 10 mg to about 500 mg of the compound.