Dna-pk inhibitors

A method of inhibiting or suppressing repair of a DNA break in one or more target genomic regions via a non-homologous end joining (NHEJ) pathway, comprising:

• administering to one or more cells that comprise one or more target genomic regions, a genome editing system and
• a compound of formula (III-E-1) or (III-E-2), or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or NR;
• wherein R is H or C1-C4 alkyl;
• Y is O, or NR;
• wherein R is H or C1-C4 alkyl;
• R3 is hydrogen, C1-4 alkyl, or OC1-2 alkyl;
• R1 is a 6-membered heteroaromatic ring containing one or two nitrogen atoms wherein the heteroaromatic ring may be substituted by 0, 1, 2 or 3 substituents R2 independently selected from the group consisting of halo, CN, C1-C4-alkyl, C1-C4-haloalkyl, C3-C4-cycloalkyl, OR6, C(═O)OR6, C(═O)NR7R6, and NR4R5;
• wherein
• each C1-C4-alkyl and C1-C4-haloalkyl is substituted by 0, 1, or 2 OR6 groups,
• each R6 and R7 is independently H, C1-C4 alkyl or C1-C4-haloalkyl,
• each R4 and R5 is independently H, C1C4 alkyl, or C(═O)C1-C4 alkyl;
• or
• R4 and R5 together with the N atom to which they are attached form a heterocyclic ring comprising 0 or 1 additional O or N atom wherein said heterocyclic ring may be substituted by C1-C4 alkyl or OR6;
• and
• Ring B is selected from the group consisting of:
• wherein W is N or CR7;
• and Z is O or S;
• wherein R7 is H or C1-C4 alkyl,
• wherein the genome editing system interacts with a nucleic acid(s) of the one or more target genomic regions, resulting in a DNA break, and wherein repair of the DNA break via a NHEJ pathway is inhibited or suppressed.

A method of modifying expression of one or more genes or proteins comprising:

• administering to one or more cells that comprise one or more target genomic regions, a genome editing system and
• a compound of formula (III-E-1) or (III-E-2), or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or NR;
• wherein R is H or C1-C4 alkyl;
• Y is O, or NR;
• wherein R is H or C1-C4 alkyl;
• R3 is hydrogen, C1-4 alkyl, or OC1-2 alkyl;
• R1 is a 6-membered heteroaromatic ring containing one or two nitrogen atoms wherein the heteroaromatic ring may be substituted by 0, 1, 2 or 3 substituents R2 independently selected from the group consisting of halo, CN, C1-C4-alkyl, C1-C4-haloalkyl, C3-C4-cycloalkyl, OR6, C(═O)OR6, C(═O)NR7R6, and NR4R5;
• wherein
• each C1-C4-alkyl and C1-C4-haloalkyl is substituted by 0, 1, or 2 OR6 groups,
• each R6 and R7 is independently H, C1-C4 alkyl or C1-C4-haloalkyl,
• each R4 and R5 is independently H, C1C4 alkyl, or C(═O)C1-C4 alkyl;
• or
• R4 and R5 together with the N atom to which they are attached form a heterocyclic ring comprising 0 or 1 additional O or N atom wherein said heterocyclic ring may be substituted by C1-C4 alkyl or OR6;
• and
• Ring B is selected from the grout) consisting of:
• wherein W is N or CR7;
• and Z is O or S;
• wherein R7 is H or C1-C4 alkyl,
• wherein the genome editing system interacts with a nucleic acid(s) of the one or more target genomic regions of a target gene(s), resulting in editing the one or more target genomic regions and wherein the edit modifies expression of a downstream gene(s) and/or protein(s) associated with the target gene(s).

A kit or composition for editing one or more target genomic regions, comprising:

• a genome editing system;
• and
• a compound of formula (III-E-1) or (III-E-2), or a pharmaceutically acceptable salt thereof,
• wherein:
• X is O or NR;
• wherein R is H or C1-C4 alkyl;
• Y is O, or NR;
• wherein R is H or C1-C4 alkyl;
• R3 is hydrogen, C1-4 alkyl, or OC1-2 alkyl;
• R1 is a 6-membered heteroaromatic ring containing one or two nitrogen atoms wherein the heteroaromatic ring may be substituted by 0, 1, 2 or 3 substituents R2 independently selected from the group consisting of halo, CN, C1-C4-alkyl, C1-C4-haloalkyl, C3-C4-cycloalkyl, OR6, C(═O)0R6, C(═O)NR7R6, and NR4R5;
• wherein
• each C1-C4-alkyl and C1-C4-haloalkyl is substituted by 0, 1, or 2 OR6 groups,
• each R6 and R7 is independently H, C1-C4 alkyl or C1-C4-haloalkyl,
• each R4 and R5 is independently H, C1-C4 alkyl, or C(═O)C1-C4 alkyl;
• or
• R4 and R5 together with the N atom to which they are attached form a heterocyclic ring comprising 0 or 1 additional O or N atom wherein said heterocyclic ring may be substituted by C1-C4 alkyl or OR6;
• and
• Ring B is selected from the group consisting of:
• wherein W is N or CR7;
• and Z is O or S;
• wherein R7 is H or C1-C4 alkyl.