Compositions and methods for the treatment of cancer

A method for the treatment of proliferative diseases, including cancer, which comprises administering to a mammalian specie in need thereof a therapeutically effective amount of (1) at least one anti-proliferative agent(s) and (2) a compound of Formula I:

• 3
• and pharmaceutically acceptable salts, wherein:
• R1 and R2 are, independently, hydrogen, fluorine or alkyl;
• R3 is aryl or heteroaryl
• R4 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl;
• or
• CO-alkyl, CO-cycloalkyl, CO-aryl, CO-alkyl-cycloalkyl, CO-alkyl-aryl, CO-heteroaryl, CO-alkyl-heteroaryl, CO-heterocycloalkyl, CO-alkyl-heterocycloalkyl;
• or
• CONH-alkyl, CONH-cycloalkyl, CONH-aryl, CONH-alkyl-cycloalkyl, CONH-alkyl-aryl, CONH-heteroaryl, CONH-alkyl-heteroaryl, CONH-heterocycloalkyl, CONH-alkyl-heterocycloalkyl;
• or
• COO-alkyl, COO-cycloalkyl, COO-aryl, COO-alkyl-cycloalkyl, COO-alkyl-aryl, COO-heteroaryl, COO-alkyl-heteroaryl, COO-heterocycloalkyl, COO-alkyl-heterocycloalkyl;
• or SO2-alkyl, SO2-cycloalkyl, SO2-aryl, SO2-alkyl-cycloalkyl, SO2-alkyl-aryl, SO2-heteroaryl, SO2-alkyl,- heteroaryl, SO2-heterocycloalkyl, SO2-alkyl-heterocycloalkyl;
• or
• C(NCN)NH-alkyl, C(NCN)NH-cycloalkyl, C(NCN)NH-aryl, C(NCNNH)-alkyl-cycloalkyl, C(NCN)NH-alkyl-aryl, C(NCN)NH-heteroaryl, C(NCN)NH-alkyl-heteroaryl, C(NCN)NH-heterocycloalkyl, C(NCN)NH-alkyl-heterocylcoalkyl;
• or
• C(NNO,)NH-alkyl, C(NNO,)NH-cycloalkyl, C(NN0,) NH-aryl, C(NNO.)NH-alkyl-cycloalkyl, C(NNO,)NH-alkyl-aryl, C(NNO,)NH-heteroaryl, C(NNO,)NH-alkyl-heteroaryl, C(NNO,)NH-heterocyloalkyl, C(NNO,)NH-alkyl-heterocycloalkyl;
• or
• C(NH)NH-alkyl, C(NH)NH-cycloalkyl, C(NH)NH-aryl, C(NH)NH-alkyl-cycloalkyl, C(NH)NH-alkyl-aryl, C(NH) NH-heteroaryl, C(NH)NH-alkyl-heteroaryl, C(NH)NH-heterocycloalkyl, C(NH)NH-alkyl-heterocycloalkyl;
• or
• C(NH)NHCO-alkyl, C(NH)NHCO-cycloalkyl, C(NH) NHCO-aryl, C(NH)NHCO-alkyl-cycloalkyl, C(NH)NHCO-alkyl-aryl, C(NH)NHCO-heteroaryl, C(NH)NHCO-alkyl-heteroaryl, C(NH)NHCO-heterocylcloalkyl, C(NH)NHCO-alkyl-heterocycloalkyl;
• or
• C(NOR6)NH-alkyl, C(NOR6)NH-cycloalkyl, C(NOR6) NH-aryl, C(NOR6)NH-alkyl-cycloalkyl, C(NOR6)NH-alkyl-aryl, C(NOR6)NH-heteroaryl, C(NOR6)NH-alkyl-heteroaryl, C(NOR6)NH-heterocylcoalkyl, C(NOR6)NH-alkyl-heterocycloalkyl;
• R5 is hydrogen or alkyl;
• R6 is hydrogen, alkyl, cycloalkyl, aryl, cycloalkylakyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkylalkyl;
• heterocycloalkyl or
• m is an integer of 0 to 2;
• and
• n is an integer of 1 to 3.