Curcusone diterpenoids and uses thereof

A method of using a compound of Formula III as a BRCA1-associated ATM activator 1 (BRAT1) inhibitor, wherein the compound of Formula III is:

• or any stereoisomer, any pharmaceutically acceptable salt thereof,
• wherein R1 and R3 are each independently CN, CO2R4, CONR5R6, an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, R2 is H, —(SO2)—R7, or —(C═O)—R7, wherein R4, R5, and R6 are each independently H, or an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, wherein R7 is an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, or R7 is NR8R9, wherein R8 and R9 are each independently H, an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, or R8 and R9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S.

A compound of Formula III:

• or a pharmaceutically acceptable salt thereof,
• wherein R1 and R3 are each independently CN, CO2R4, CONR5R6, an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, R2 is H, —(SO2)—R7, or —(C═O)—R7, wherein R4, R5, and R6 are each independently H, or an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, wherein R7 is an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, or R7 is NR8R9, wherein R8 and R9 are each independently H, an optionally substituted C1-C6 straight or branched alkyl group, or an optionally substituted C3-C6 carbon ring, wherein 1 or 2 carbon of the C3-C6 carbon ring can be replaced by N, O, or a combination thereof, or R8 and R9 can jointly form an nitrogen-containing 3-8 membered ring, wherein the ring can have 1-3 hetero atom selected from the group consisting of O, N, and S,
• provided that the compound is not:
• or any stereoisomer thereof.

A synthetic method to prepare a curcusone compound D or an isomer thereof, comprising:

• providing a compound of Formula A and treating the compound of Formula A under a halogenation condition to provide a compound of Formula B;
• treating the compound of Formula B under a first methylation condition to provide a compound of Formula C, or any isomer thereof;
• and
• treating the compound of Formula C under a second methylation condition to provide a compound of Formula D or an isomer thereof, wherein X is Cl, Br, or I.