Substituted 2-Alkyl Quinazolinone Derivatives as Parp Inhibitors

A method of treating a PARP mediated disorder in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I)

• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
• the dotted lines represent optional bonds;
• X is >N—, >CH— or >CR2— wherein R2 is aminocarbonyl;
• or when X is >CR2— then R2 taken together with -L-Z can form a bivalent radical of formula
• —C(O)—NH—CH2—NR10— (a-1)
• wherein R10 is phenyl;
• is —N—C(O)— or >—N═CR4—, wherein R4 is hydroxy;
• R1 is hydrogen, halo, C1-6alkyloxy or C1-6alkyl;
• R3 is hydrogen, or C1-6alkyloxy;
• Z is a radical selected from
• wherein each R5, R6, R7 and R8 is independently selected from hydrogen, halo, amino, C1-6alkyl or C1-6alkyloxy;
• or
• R7 and R8 taken together may form a bivalent radical of formula
• —CH2—CR92—O— (c-1),
• —(CH2)3—O— (c-2),
• —O—(CH2)2—O— (c-3)or
• —CH═CH—CH═CH— (c-4)
• wherein each R9 is independently selected from hydrogen or C1-6alkyl;
• and
• L is a bivalent radical selected from —C(O)—, —C(O)—NH—, —C(O)—C1-6alkanediyl- or —C(O)—O—C1-6alkanediyl-;
• or
• L can be a direct bond when X is >CR2— or when Z is a radical of formula (b-11).

A combination of a compound with a chemotherapeutic agent, wherein said compound is a compound of formula (I):

• the N-oxide forms the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
• the dotted lines represent optional bonds;
• X is >N—, >CH— or >CR— wherein R2 is aminocarbonyl;
• or when X is >CR2— then R2 taken together with -L-Z can form a bivalent radical of formula
• —C(O)—NH—CH2—NR10— (a- 1)
• wherein R10 is phenyl;
• is —N—C(O)— or —N═CR4—, wherein R4 is hydroxy;
• R1 is hydrogen halo, C1-6alkyloxy or C1-6alkyl;
• R3 is hydrogen or C1-6alkyloxy;
• Z is a radical selected from
• wherein each R5 R6 R7 and R8 is independently selected from hydrogen halo, amino C1-6alkyl or C 1-6alkyloxy or
• R7 and R8 taken together may form a bivalent radical of formula
• CH2—CR92—O— (c-1),
• —(CH2)3—O— (c-2)
• —O—(CH2)2—O— (c-3)or
• —CH═CH—CH═CH— (c-4)
• wherein each R9 is independently selected from hydrogen or C1-6alkyl;
• and
• L is a bivalent radical selected from —C(O)—, —C(O)—NH— —C(O)—C1-6alkanediyl- or —C(O)—O—C1-6alkanediyl-;
• or
• L can be a direct bond when X is >CR2— or when Z is a radical of formula (b-11).