TRICYCLIC PHTHALAZINONE PARP INHIBITORS AND METHODS OF USE
The present disclosure relates to compounds according to Formula I or a pharmaceutically acceptable salt and/or solvate thereof, as well as compositions including such compounds and uses thereof, where X 1 is H, F, or Cl; X 2 is NH or N—R 3 ; one of R 1 and R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, and the remaining one of R 1 and R 2 is aryl, heteroaryl, or non-aromatic heterocyclyl; and R 3 is alkyl, cycloalkyl, alkylenyl, and non-aromatic heterocyclyl. Among other things, the present disclosure evidences compounds of the present disclosure penetrate the central nervous system allowing for treatment of central nervous system cancers.
1 . A compound of Formula I
or a pharmaceutically acceptable salt and/or solvate thereof, wherein
X 1 is H, F, or Cl;
X 2 is NH or N—R 3 ;
one of R 1 and R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, and the remaining one of R 1 and R 2 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 3 is alkyl, cycloalkyl, alkylenyl, and non-aromatic heterocyclyl.
2 . The compound of claim 1 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.
3 . The compound of claim 1 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.
4 . The compound of claim 1 , wherein X 1 is F.
5 . The compound of claim 1 , wherein X 2 is NH.
6 . The compound of claim 1 , wherein the compound is of Formula IA
or a pharmaceutically acceptable salt and/or solvate thereof.
7 . The compound of claim 6 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.
8 . The compound of claim 7 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.
9 . The compound of claim 8 , wherein X 1 is F.
10 . The compound of claim 9 , wherein X 2 is NH.
11 . The compound of claim 1 , wherein the compound is of Formula IB
or a pharmaceutically acceptable salt and/or solvate thereof.
12 . The compound of claim 11 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, or non-aromatic heterocyclyl.
13 . The compound of claim 12 , wherein
R 1 is aryl, heteroaryl, or non-aromatic heterocyclyl; and
R 2 is H, alkyl, cycloalkyl, or non-aromatic heterocyclyl.
14 . The compound of claim 13 , wherein X 1 is F.
15 . The compound of claim 14 , wherein X 2 is NH.
16 . A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 , wherein the effective amount of the compound is effective to treat a cancer.
18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , wherein the compound is present in an amount effective to treat the cancer when combined with a second cancer therapy.
19 . A method of treating a subject suffering from a B-cell malignancy, the method comprising administering to the subject an effective amount of a compound of claim 1 and an effective amount of a second cancer therapy.
20 .- 23 . (canceled)
24 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt and/or solvate of any one thereof.