Ku inhibitors and their use

A method of gene editing comprising

• a. contacting a compound of the formula II
• wherein
• Z is O or S;
• R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, —OR6, —CN, —NO2, —C(O)R6, —CO2R6, —C(O)NR6R7, —OS(O)R6, —OS(O)2R6, —SR6, —S(O)R6, —S(O)2R6, —S(O)NR6R7, —S(O)2NR6R7, —OS(O)NR6R7, —OS(O)2NR6R7, and —NR6R7;
• wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is independently optionally substituted with halogen;
• R3 is H, halogen, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted with halogen;
• Y is —C(O)NR4R5 or phenyl, wherein each hydrogen atom in phenyl is optionally substituted with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, —OR4, —CN, —NO2, —C(O)R4, —CO2R4, —C(O)NR4R5, —OS(O)R4, —OS(O)2R4, —SR4, —S(O)R4, —S(O)2R4, —S(O)NR4R5, —S(O)2NR4R5, —OS(O)NR4R5, —OS(O)2NR4R5, and —NR4R5, or two adjacent hydrogen atoms on phenyl are optionally substituted with a group that combines with the carbon atoms to which they are attached to form a 5- to 7-membered heterocycloalkyl ring;
• R4 and R5 are each independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6 alkyl-(C3-C6 cycloalkyl), —C1-C6 alkyl-(C6-C10 aryl), 3- to 7-membered heterocycloalkyl, C6-C10 aryl and 5- to 7-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6 alkyl-(C3-C6 cycloalkyl) or —C1-C6 alkyl-(C6-C10 aryl) is independently optionally substituted with halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, —OR8, —CN, —NO2, —C(O)R8, —CO2R8, —C(O)NR8R9, —OS(O)R8, —OS(O)2R8, —SR8, —S(O)R8, —S(O)2R8, —S(O)NR8R9, —S(O)2NR8R9, —OS(O)NR8R9, —OS(O)2NR8R9, and —NR8R9;
• each R6, R7, R8 and R9 is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6 alkyl-(C3-C6 cycloalkyl), —C1-C6 alkyl-(C6-C10 aryl), 3- to 7-membered heterocycloalkyl and C6-C10 aryl;
• C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —C1-C6 alkyl-(C3-C6 cycloalkyl) or —C1-C6 alkyl-(C6-C10 aryl) is independently optionally substituted with halogen, and
• is either a single bond or a pi-bond, with at least one cell comprising at least one programmable nuclease.