Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof
A phthalazinone ketone derivative as represented by formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, a use thereof as a poly (ADP-ribose) polymerase (PARP) inhibitor, and a cancer treatment method thereof are described.
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
A and B are taken together with the attached carbon atoms to form an aryl or heteroaryl, wherein said aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of an alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
R 1 , R 2 , R 3 or R 4 is each independently selected from the group consisting of hydrogen, a halogen, alkyl, cyano and alkoxyl, wherein said alkyl or alkoxyl is each independently and optionally substituted with one or more groups selected from the group consisting of a halogen, hydroxyl, alkyl and alkoxyl;
D, E, or G is each independently selected from the group consisting of nitrogen atom and C(R 8 );
R 5 is selected from the group consisting of hydrogen, an alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of an alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
R 6 or R 7 is each independently selected from the group consisting of hydrogen, an alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is each independently and optionally substituted with one or more groups selected from the group consisting of an alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
alternatively, R 6 and R 7 are taken together with the attached N atom to form a heterocyclyl, wherein said heterocyclyl contains one or more N, O or S(O) m heteroatoms, and said heterocyclyl is optionally substituted with one or more groups selected from the group consisting of an alkyl, halogen, hydroxyl alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and alkoxycarbonyl;
R 8 is selected from the group consisting of hydrogen, an alkyl, halogen, hydroxyl, cyano, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —(CH 2 ) n NR 6 R 7 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 , wherein said alkyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or benzyl is each independently and optionally substituted with one or more groups selected from the group consisting of an alkyl, halogen, hydroxyl, alkoxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —C(O)OR 5 , —OC(O)R 5 , —O(CH 2 ) n C(O)OR 5 , —C(O)R 5 , —NHC(O)R 5 , —NR 6 R 7 , —OC(O)NR 6 R 7 and —C(O)NR 6 R 7 ;
m is selected from the group consisting of 0, 1 and 2; and
n is selected from the group consisting of 0, 1 and 2.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein A and B are taken together with the attached carbon atoms to form an aryl.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is hydrogen.
4. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is a halogen.
5. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 8 is selected from the group consisting of hydrogen, an alkyl, halogen, cyano, —C(O)OR 5 , —(CH 2 ) n NR 6 R 7 and —C(O)NR 6 R 7 , wherein said alkyl is optionally substituted with one or more halogen atoms.
6. The compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein R 8 is trifluoromethyl.
7. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 , R 2 , R 3 or R 4 is each independently hydrogen.
8. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 , R 3 or R 4 is each independently hydrogen, and R 1 is a halogen.
9. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of:
10. The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein the aryl formed from A and B taken together is phenyl.
11. The compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 1 is a fluorine atom.
12. The compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein R 1 is a fluorine atom.
13. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier or excipient.