Oxynitidine derivatives useful as inhibitors of topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1)

A compound of Formula I or a pharmaceutically acceptable salt thereof,

• wherein
• the group
• is
• in which Z is O or S;
• and
• R is hydroxyl, amino, mono- or di-C1-C6alkylamino;
• or
• R is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl, each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, C1-C2alkyl, and C1-C2alkoxy;
• or
• the group
• is
• in which Z is NH or NR10;
• and
• R is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl, each of which is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, C1-C2alkyl, and C1-C2alkoxy;
• and
• L is C2-C3 alkyl;
• R1, R2, and R3 are independently chosen from hydrogen, hydroxyl, halogen, amino, C1-C6alkyl, C1-C6alkoxy, benzyloxy, C1-C6alkylthio, C1-C2haloalkyl, and C1-C2haloalkoxy;
• or
• R1 and R2 can be taken together to form a 5 or 6-membered heterocycloalkyl ring containing 2 oxygen atoms, which R1/R2 ring is unsubstituted or substituted with 1 or 2 independently chosen R5 substituents, where R5 is independently chosen at each occurrence from halogen, hydroxyl, C1-C2alkyl, and C1-C2alkoxy;
• or
• R2 and R3 can be taken together to form a 5 or 6-membered heterocycloalkyl ring containing 2 oxygen atoms, which R2/R3 ring is unsubstituted or substituted with 1 or 2 independently chosen R5 substituents;
• R4, R6, R7, R8, and R9 are independently chosen from hydrogen, halogen, hydroxyl, amino, cyano, COOH, CHO, or C1-C6alkyl, which C1-C6alkyl can contain one or more double or triple bonds, can have one or more CH2 group replaced by NH, NR10, S, or O, and is optionally substituted with one or more substituents independently chosen from hydroxyl, amino, cyano, halogen, oxo, and C3-C6cycloalkyl;
• R10 is C1-C6alkyl or (C3-C6cycloalkyl)C0-C4alkyl;
• R11 and R12 are independently chosen from hydrogen, hydroxyl, halogen, amino, C-C6alkyl, C1-C6alkoxy, benzyloxy, C1-C6alkylthio, C1-C2haloalkyl, or C1-C2haloalkoxy;
• or
• R11 and R12 can be taken together to form a 5 or 6-membered heterocycloalkyl ring containing 2 oxygen atoms, which R11/R12 ring is unsubstituted or substituted with 1 or 2 independently chosen R5 substituents.