Compounds and compositions that cause mycn and/or cmyc degradation and methods of use thereof

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (I):

• wherein:
• a dashed line indicates the presence of an optional double bond;
• X is selected from the group consisting of no atom, H, and O;
• R1 and R2 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R1 and R2 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• R3 and R4 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R3 and R4 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• and
• R5 is selected from the group consisting of NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O);
• N(R)SO2, SO2N(R), S, SO, SO2, -(optionally substituted C1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R is selected from the group consisting of H, D, O, halo, aryl, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of —OH, halo, C1-4alkyl, CF3, and combinations thereof,
• or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof,
• with the proviso that the compound is not

A method for treating or ameliorating the effects of a cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (I):

• wherein:
• a dashed line indicates the presence of an optional double bond;
• X is selected from the group consisting of no atom, H, and O;
• R1 and R2 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R1 and R2 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• R3 and R4 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R3 and R4 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• and
• R5 is selected from the group consisting of NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O);
• N(R)SO2, SO2N(R), S, SO, SO2, -(optionally substituted C1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R is selected from the group consisting of H, D, O, halo, aryl, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of —OH, halo, C1-4alkyl, CF3, and combinations thereof, or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

A method for selectively killing a cancer cell, comprising contacting the cancer cell with an effective amount of a compound having the structure of formula (I):

• wherein:
• a dashed line indicates the presence of an optional double bond;
• X is selected from the group consisting of no atom, H, and O;
• R1 and R2 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R1 and R2 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• R3 and R4 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R3 and R4 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• and
• R5 is selected from the group consisting of NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O);
• N(R)SO2, SO2N(R), S, SO, SO2, -(optionally substituted C1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R is selected from the group consisting of H, D, O, halo, aryl, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of —OH, halo, C1-4alkyl, CF3, and combinations thereof,
• or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

A method of modulating mTORC1/2 signaling activity in a cell, comprising contacting the cell with an effective amount of a compound having the structure of formula (I):

• wherein:
• a dashed line indicates the presence of an optional double bond;
• X is selected from the group consisting of no atom, H, and O;
• R1 and R2 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R1 and R2 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• R3 and R4 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R3 and R4 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• and
• R5 is selected from the group consisting of NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O);
• N(R)SO2, SO2N(R), S, SO, SO2, -(optionally substituted C1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R is selected from the group consisting of H, D, O, halo, aryl, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of —OH, halo, C1-4 alkyl, CF3, and combinations thereof, or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

A method of modulating the activity of a Master Regulator for MycN in a subject having MycN-amplified neuroblastoma (MycNAMP NBL), comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula (I):

• wherein:
• a dashed line indicates the presence of an optional double bond;
• X is selected from the group consisting of no atom, H, and O;
• R1 and R2 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R1 and R2 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• R3 and R4 are independently selected from the group consisting of no atom, H, D, —OH, N, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of N, epoxy, —OH, halo, C1-4alkyl, CF3, and combinations thereof, or R3 and R4 may together form a C3-10carbocycle that may be optionally substituted with an atom or a group selected from the group consisting of O, N, halo, C1-4alkyl, CF3, and combinations thereof;
• and
• R5 is selected from the group consisting of NR, N(R)C(O), C(O)NR, O, C(O), C(O)O, OC(O);
• N(R)SO2, SO2N(R), S, SO, SO2, -(optionally substituted C1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), wherein R is selected from the group consisting of H, D, O, halo, aryl, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C2-6alkenyl, C2-6alkenyl-aryl, and C2-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of —OH, halo, C1-4alkyl, CF3, and combinations thereof, or an N-oxide, crystalline form, hydrate thereof, or a pharmaceutically acceptable salt thereof.

A method for identifying a compound that induces degradation of a cancer-related protein, comprising the steps of:

• (a) obtaining cancer cell lines that express the protein (AMP cell lines) and cancer cell lines that do not express the protein (NULL cell lines);
• (b) identifying compounds that are lethal to at least one of the cell lines;
• (c) identifying compounds that are selective for AMP cell lines from those identified in step (b) based on cell line subtype selectivity;
• (d) determining the expression level of the protein in AMP cell lines for each selective compound identified in step (c) by performing a high-throughput gene expression profiling;
• and
• (e) identifying a candidate compound that induces degradation of the cancer-related protein based on the result of step (d).