# US 11,028,084 B2 · Selective inhibitors of gentotoxic steress-induced IKK/NF-κB pathways > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,028,084 B2 - Document ID: US11028084B2 - Status: Granted - Kind: B2 - Application number: 16/349,580 - Filed: 2017-11-14 - Published: 2019-09-12 - Granted: 2021-06-08 - Earliest claimed: 2016-11-14 - Assignees: Max-DelbrüCk-Centrum FüR Molekulare Medizin In Der Helmholtz-Gemeinschaft; Forschungsverbund Berlin E.V. - Applicants: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft; Forschungsverbund Berlin e.V. - Inventors: Claus Scheidereit; Michael Willenbrock; Peter Lindemann; Silke Radetzki; Jens-Peter Von Kries; Marc Nazare - Web page: https://patentgrep.com/patent/US11028084B2 ## CPC - C07D 471/04: Ortho-condensed systems - A61P 35/00: Antineoplastic agents - C07D 209/56: Ring systems containing three or more rings - C07D 221/06: Ring systems of three rings - C07D 471/14: Ortho-condensed systems - C07D 471/16: Peri-condensed systems - C07D 487/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A method is for treatment of a disease associated with genotoxic stress-induced inhibitor of nuclear factor-κB kinase/nuclear factor kappa-light chain enhancer of activated B cells (IKK/NF-κB) signaling. The method can include administering a compound to a subject having a cancer exhibiting genotoxic stress induced IKK/NF-κB activation. ## Claims ### Claim 1 A method of treatment of a cancer in a subject in need thereof comprising: (a) identifying the subject as having a cancer exhibiting genotoxic stress-induced IKK/NF-κB signaling activation that causes growth of the cancer, (b) selectively blocking activation of IKK/NF-κB in response to the genotoxic stress upstream of the IKK complex in the subject without blocking NF-κB activation upon signaling caused by other pathways in the subject by administering to the subject a compound according to Formula I, wherein R1=H, O; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide; R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms; X1 and X2=N or C; X3=C; ring A is an aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms selected from the group consisting of O and N, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, alkoxycarbonyl, amine, aryl, (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine) and alkoxyamine; the bond z may be present or not present, wherein when bond z is not present: the C of bond z of ring C is potentially substituted with R3, and X3 of the A ring is optionally substituted with H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine. ### Claim 2 (depends on 1) The method according to claim 1, wherein the compound is, according to Formula II, wherein R1=H, O; R5=H, halogen, C1-C5, alkyl, alkenyl, alkoxy, amine; R6=H, OH, halogen, C1-C5, alkyl, alkoxy, or alkoxyamine, alkoxyamide; R7=H, halogen, C1-C5, alkyl, or alkoxy; R8=H, halogen, C1-C5, alkyl or alkoxy; R9=H, halogen, C1-C5, alkyl or alkoxy; R10=H, halogen, C1-C5, alkyl or alkoxy; R11=H, halogen, C1-C5, alkyl, alkoxy, or carboxyl; R12=H, halogen, C1-C5, alkyl or alkoxy; or wherein when X1 is C, R9 and R10, R10 and R11, R11 and R12, or R12 and the C in the position of bond z of ring C, form an optionally aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms or forming phenyl; X1=N or C; X3=C; ring A is an aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms selected from the group consisting of 0 and N, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl, (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine), and alkoxyamine; the bond z may be present or not present, wherein when bond z is not present: the C in the position of bond z of ring C is substituted with halogen, preferably Cl, Br, F, C1-C7, alkyl, and X3 of the A ring is optionally substituted with H, C1-C5, alkyl, or when X3 is C with H, C1-C5, alkyl, OH, halogen. ### Claim 3 (depends on 1) The method according to claim 1, wherein R1=0. ### Claim 4 (depends on 1) The method according to claim 1, wherein at least one of R2 from 0-4 is not H. ### Claim 5 (depends on 1) The method according to claim 1, wherein ring A is a heteroaromatic cyclic structure of 6 members, comprising 1 or 2 heteroatoms selected from 0 and/or N. ### Claim 6 (depends on 1) The method according to claim 1, wherein ring A is selected from the group consisting of ### Claim 7 Compound according to Formula I, wherein: R1=0; R5=H, halogen, C1-C5 alkyl or alkoxy, or amine; R6=H, OH, halogen, C1-C5 alkyl or alkoxy; R7=H, halogen, C1-C5 alkyl or alkoxy; R8=halogen, C1-C5 alkyl or alkoxy, wherein at least one of R5 to R8 is not H; R9=H, halogen, or C1-C5 alkyl or alkoxy; R10=H, halogen, or C1-C5 alkyl or alkoxy; R11=H, halogen, C1-C5 alkyl, alkoxy or carbonyl; R12=H, halogen, or C1-C5 alkyl or alkoxy; or wherein when X1 is C, R9 and R10, R10 and R11, R11 and R12, or R12 and the C in the position of bond z of ring C, form an optionally aromatic cyclic structure of 5 or 6 members, comprising 0, 1, or 2 heteroatoms or forming phenyl; X1=N or C; X3=C; ring A is a heteroaromatic cyclic structure of 6 members, comprising 1 or 2 heteroatoms selected from 0 and/or N, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl and alkoxyamine; the bond z may be present or not present, wherein when bond z is not present; and the C in the position of bond z of ring C is substituted with halogen or C1-C5 alkyl, or X3 of the A ring is optionally substituted with H, C1-C5 alkyl, OH or halogen. ### Claim 8 (depends on 7) Compound according to claim 7, wherein the compound is of Formula III, wherein R1=0; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine or alkoxyamide, wherein at least one of R2 from 0-4 is not H; R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or forming phenyl; X1=N or C; X3=C; ring A is a heteroaromatic structure of 6 members, comprising 1 or 2 N atom, wherein said cyclic structure is optionally substituted with 0-3 substituents that can be the same or different, selected from the group consisting of H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, aryl (optionally substituted with halogen, C1-C3 alkyl, alkoxy, amine), alkoxyamine, or wherein ring A is a heteroaromatic structure selected from the group consisting of: and ### Claim 9 (depends on 7) Compound according to claim 7, wherein the compound is of Formula VIII, wherein R1=O; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide, wherein at least one of R2 from 0-4 is not H; R3=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or form phenyl; X1=N or C; X4=N or C, whereby at least one X4 is N; R16=can be 0-3, the same or different, H, halogen, C1-C5 alkoxy. ### Claim 10 (depends on 7) Compound according to claim 7, wherein the compound is of Formula IX, wherein R1=O; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide, wherein at least one of R2 from 0-4 is not H; R3=from 0-4, can be the same or different, H, OH, halogen C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or form phenyl; X1=N or C; R16=can be 0-3, the same or different, H, halogen, C1-C5, alkyl or alkoxy. ### Claim 11 (depends on 7) Compound according to claim 7, wherein the compound is of Formula X, wherein R1=O; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide, wherein at least one of R2 from 0-4 is not H; R3=from 0-4, can be the same or different, H, OH, halogen C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or form phenyl; X1=N or C; R16=can be 0-3, the same or different, H, halogen, C1-C5 alkyl, alkoxy or methoxy. ### Claim 12 (depends on 7) Compound according to claim 7, wherein the compound is of Formula VI, wherein R1=O; R2=from 0-4, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein R2 is alkoxyamine, alkoxyamide, wherein at least one of R2 from 0-4 is not H; R3=from 0-4, preferably 0, 1, 2, can be the same or different, H, OH, halogen, C1-C7 alkyl, alkenyl, alkynyl, alkoxy, carbonyl, carboxyl, alkoxycarbonyl, amine, or wherein two (adjacent) R3 substituents can form an optionally aromatic cyclic structure of 5 or 6 members, optionally comprising 0, 1, or 2 heteroatoms or form phenyl; X1=N or C; R16=can be 0-3, the same or different, H, halogen, C1-C5 alkoxy. ### Claim 13 (depends on 1) The method according to claim 1, wherein the compound is ### Claim 14 (depends on 1) The method according to claim 1, wherein the compound is more effective in inhibiting NF-κB-signaling induced by genotoxic stress compared to inhibiting NF-κB-signaling induced by TNF-alpha and/or IL-1 ß. ### Claim 15 (depends on 1) The method according to claim 1, wherein the disease is associated with genomic instability due to defective DNA-repair mechanisms. ### Claim 16 (depends on 1) The method according to claim 1, wherein said cancer is associated with NF-κB-mediated resistance to therapy-induced tumor cell apoptosis. ### Claim 17 (depends on 1) The method according to claim 1, wherein the compound is administered in combination with one or more genotoxic stress-inducing (DNA damage-inducing) cancer therapies. ### Claim 18 (depends on 1) In vitro method for the inhibition of genotoxic stress-induced NF-κB signaling or inhibition of DNA repair mechanisms comprising the use of a compound according to claim 1. ### Claim 19 (depends on 1) The method of claim 1, wherein the genotoxic stress-induced IKK/NF-κB signaling pathway is activated by a factor selected from the group consisting of a pro-inflammatory cytokine, PAMPS (pathogen associated molecular patterns), engagement of immune receptors and γ-irradiation (γ-IR).