Tricyclic compounds as mrp1-inhibitors

A method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I:

• 12
• where
• 13
• Y is -E-C(O)R1 or -E-NR2R3;
• E is a bond or —CH2—;
• R1 is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, or NR2R4;
• R2 is independently at each occurrence hydrogen, C1-C6 alkyl, (C1-C6 alkyl)-aryl, or aryl;
• R3 is independently at each occurrence hydrogen, C1-C6 alkyl, C1-C4 alkoxy, optionally substituted heterocycle, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, C(O)C(O)R9, C(O)R5, or R2 and R3, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R4 is independently at each occurrence hydrogen, C1-C6 alkyl, C1-C4 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, or R2 and R4, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R5 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C1-C4 alkoxy)-SiCH3, optionally substituted (C1-C4 alkyl)-(C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, optionally substituted (C1-C4 alkyl)-phenoxy, (CH2)tC(R6)(R7)N(R6)(R8), or NR2R4;
• tis 0, 1, 2, 3,or 4;
• R6 is independently at each occurrence hydrogen or C1-C6 alkyl;
• R7 is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
• R8 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, C(O)OR9, C(O)R10, or R6 and R8, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R9 is independently at each occurrence hydrogen, C1-C6 allyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
• R10 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C1-C4 alkoxy)-SiCH3, optionally substituted (C1-C4 alkyl)-(C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, or optionally substituted (C1-C4 alkyl)-phenoxy;
• or a pharmaceutical salt thereof.

A method of inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance, in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I:

• 14
• where:
• 15
• Y is -E-C(O)R1 or -E-NR2R3;
• E is a bond or —CH2—;
• R1 is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, or NR2R4;
• R2 is independently at each occurrence hydrogen, C1-C6 alkyl, (C1-C6 alkyl)-aryl, or aryl;
• R3 is independently at each occurrence hydrogen, C1-C6 allyl, C1-C4 alkoxy, optionally substituted heterocycle, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, C(O)C(O)R9, C(O)R5, or R2 and R3, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R4 is independently at each occurrence hydrogen, C1-C6 alkyl, C1-C4 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, or R2 and R4, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R5 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C1-C4 alkoxy)-SiCH3, optionally substituted (C1-C4 alkyl)-(C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, optionally substituted (C1-C4 alkyl)-phenoxy, (CH2)tC(R6)(R7)N(R6)(R8), or NR2R4;
• t is 0, 1, 2, 3,or4;
• R6 is independently at each occurrence hydrogen or C1-C6 alkyl;
• R7 is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
• R8 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 bicycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, C(O)OR9, C(O)R10, or R6 and R8, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R9 is independently at each occurrence hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle;
• R10 is independently at each occurrence C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C 1-C4 alkoxy)-SiCH3, optionally substituted (C1-C4 alkyl)-(C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted heterocycle, or optionally substituted (C1-C4 alkyl)-phenoxy;
• or a pharmaceutical salt thereof;
• in combination with an effective amount of one or more oncolytic agents.