Xanthones, thioxanthones and acridinones as dna-pk inhibitors

A DNA-PK inhibitor having a formula:

• or a pharmaceutically acceptable salt thereof,
• wherein m is an integer 0 through 3;
• n is an integer 0 through 4;
• X is 0 or NRa;
• Z, independently, is CRb or N;
• L is selected from the group consisting of alkylene, substituted alkylene, carbonyl, carbamoyl, —NRd—, —N(Rd)2, —O(SO2)Rd, —SO2Rd, oxy (—O—), thio (—S—), thionyl (—SO—), and sulfonyl;
• A is absent, or A is heteroaryl or a four- to seven-membered aliphatic ring containing 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S;
• R1, independently, is selected from the group consisting of halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, N(Rd)2, ORd, carboxyl, carboxy, nitro, OC1-3alkyleneN(Rd)2, N(Rd)1-3alkyleneN(Rd)2, OC1-3alkyleneC(═O)ORd, O(C1-3alkylene)OP(═O)(OR)2, O(C1-3alkylene)OP(═O)(ONa)2, OP(═O)(ORd)2, OP(═O)(ONa)2, cyano, aldehyde, carboxamide, thiocarboxamide, acyl, mercapto, sulfonyl, trifluoromethyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• or
• two R1 groups are taken together with the atoms to which each is attached to form a 5-, 6-, or 7-membered ring, wherein 1 or 2 carbon atoms of R1 optionally is a heteroatom selected from the group consisting of O, N, and S, said ring optionally substituted with one or more of ═O, ═S, ═NH, ORC, N(Rd)2, carboxyl, carboxy, alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and said heteroaryl optionally substituted with a substituent selected from the group consisting of aryl, substituted aryl, alkyl, substituted alkyl, and acyl;
• R2, independently, is selected from the group consisting of ORd, halo, N(Rd)2, aldehyde, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl C1-3alkyleneORd, C(═O)N(R)2, N(Rd)2, (C═O)ORd, NO2, NRdC(═O)Rd, NRd(SO2)Rd, OC1-3alkyleneORd, OC1-3alkyleneOC1-3alkyleneRd, OC(═O)Rd, OC1-3alkyleneC(═O)C1-3alkyleneRd, and(SO3)Rd;
• Ra is selected from the group consisting of hydro, C1-4alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-3alkylenearyl, C1-3alkyleneheteroaryl,C1-3alkyleneheterocycloalkyl, C1-4alkylene-N(Rd)2, C1-4alkyleneORd;
• C1-4alkyleneC(═O)ORd, C(═O)Rd, C(═O)N(Rd)2, C(═O)ORd, C(═O)SRd, C(═S)N(Rd)2, SO2Rd, SO2N(Rd)2, C(═O)NRdC1-4alkyleneORd, C(═O)NRdC1-4alkyleneheterocycloalkyl, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)heterocycloalkyl, C1-4alkyleneNRdC(═O)Rd, C1-4alkyleneOC1-4alkyleneORd, C1-4alkyleneOC1-4alkylene-C(═O)ORd, and C1-4alkyleneC(═O)N(R d)2;
• Rb, independently, is selected from the group consisting of hydro, alkyl, halo, aldehyde, ORd, O(C1-3)2, O(C1-3alkylene)OP(═O)(ONa)2, OP(═O)(ORd)2, OP(═O)(ONa)2, nitro, N(Rd)2, carboxyl, carboxy, sulfonamido, sulfamyl, and sulfo or a halide derivative thereof;
• and
• Rd, independently, is selected from the group consisting of hydro, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroocycloalkyl, substituted heterocycloalkyl, aryl, C1-3alkylenearyl, substituted aryl, heteroaryl, and substituted heteroaryl.

A DNA-PK inhibitor selected from the group consisting of:

• trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9H-xanthen-3-yl ester;
• 1-hydroxy-3-morpholin-4-yl-xanthen-9-one;
• 1-hydroxy-6-methoxy-3-trifluoromethanesulfonylxanthen-9-one ester;
• 1-hydroxy-6-methoxy-3-morpholin-4-yl-xanthen-9-one;
• 6-fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-o-one;
• 1-hydroxy-6-(4-methylpiperazin-1-yl)-3-morpholin-4-yl-xanthen-9-one;
• 1-(8-hydroxy-6-morpholin-4-yl-9-oxo-9H-xanthen-3-yl)-piperidine-4-carboxylic acid amide;
• trifluoromethanesulfonic acid 1-hydroxy-9-oxo-9,10-dihydro-acridin-3-yl ester;
• and 1-hydroxy-3-morpholin-4-yl-10H-acridi-9-one.