Bromodomain and extra-terminal protein inhibitor combination therapy

A method for treating cancer or neoplastic disease comprising administering to a human patient a therapeutically effective amount of

• (i) at least one bromodomain and extra-terminal protein (BET) inhibitor;
• and
• (ii) at least one chemotherapeutic agent, which does not inhibit BET directly,
• wherein the BET inhibitor has the structure of Formula II, or a pharmaceutically acceptable salt thereof,
• wherein:
• R2 is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;
• X5 is C—R5 or N;
• wherein
• R5 is hydrogen, halogen, OH, CN, OR61, NHR61 N(R61)2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein
• each R61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• X6 is C—H or N, provided that if X6 is N, then X5 is C—R5, and if X5 is N, then X6 is CH;
• R6 is hydrogen, halogen, OH, CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, S-alkyl, cycloalkylalkoxy, heterocyclyl, aralkoxy, heteroaryloxy, aryloxy, alkynyloxy, or N(H)COalkyl;
• RA is
• in which
• X2 is N or C—R12, wherein R12 is hydrogen, halogen, alkyl, or alkoxy;
• R13 is —Y—Z, wherein
• Y is selected from a bond, —CH2—, or —CH(C1-C4 alkyl)-, and
• Z is selected from —SO2R21, —N(R22)SO22R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
• each R21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• and
• each R22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• X3 is N or C—R14, wherein R14 is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;
• and
• X4 is N or C—R15, wherein R15 is hydrogen, halogen, alkyl, —CN, or alkoxy;
• and
• R16 is hydrogen, halogen, N(H)COX, or W-X, wherein W is a bond, O, S, or NH, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• provided that when X6 is N, then R5 and R6 are not hydrogen;
• wherein the chemotherapeutic agent is selected from the group consisting of temozolomide, romidepsin, and protein-bound paclitaxel, and wherein the BET inhibitor is present in an amount to enhance the therapeutic effect of the chemotherapeutic agent.