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:

• where:
• A is
• or
• 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;
• t is 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 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, (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;
• wherein:
• optionally substituted alkyl refers to a C1-C4 alkyl unsubstituted or substituted from 1 to 3 times with halo, C1-C4 alkanol, NH2, or hydroxy;
• optionally substituted (C1-C4 alkyl)-aryl refers to an optionally substituted aryl linked through an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)—CO-aryl refers to an optionally substituted aryl linked through a carbonyl and an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)-heterocycle refers to optionally substituted heterocycle linked through an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)-phenoxy refers to an unsubstituted or substituted phenoxy linked through an optionally substituted C1-C4 alkyl;
• optionally substituted aryl refers to an aryl group optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• optionally substituted C6-C10 bicycloalkyl refers to a C6-C10 bicycloalkyl group optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• optionally substituted C3-C8 cycloalkyl refers to a C3-C8 cycloalkyl optionally substituted once with a phenyl, substituted phenyl, hydroxy, or C1-C4 alkoxy;
• optionally substituted heterocycle refers to a heterocycle ring optionally substituted 1 or 2 times independently with a C1-C6 alkyl halo, benzyl phenyl, trifluoromethyl, or an oxo group;
• heterocycle refers to stable aromatic and non-aromatic 5- and 6-membered rings containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, said rings being optionally benzofused;
• N-heterocycle refers to a nitrogen containing heterocycle linked through a nitrogen atom;
• optionally substituted N-heterocycle refers to a heterocycle ring, linked through the nitrogen atom, optionally substituted 1 or 2 times independently with a C1-C6 alkyl, halo, benzyl, phenyl, trifluoromethyl, or an oxo group;
• substituted phenoxy refers to a phenoxy group wherein the phenyl is optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• and
• substituted phenyl refers to a phenyl group substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy.

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:

• where:
• A is
• or
• 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;
• t is 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)R9, 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, (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;
• wherein:
• optionally substituted alkyl refers to a C1-C4 alkyl unsubstituted or substituted from 1 to 3 times with halo, C1-C4 alkanol, NH2, or hydroxy;
• optionally substituted (C1-C4 alkyl)-aryl refers to an optionally substituted aryl linked through an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)—CO-aryl refers to an optionally substituted aryl linked through a carbonyl and an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)-heterocycle refers to optionally substituted heterocycle linked through an optionally substituted C1-C4 alkyl;
• optionally substituted (C1-C4 alkyl)-phenoxy refers to an unsubstituted or substituted phenoxy linked through an optionally substituted C1-C4 alkyl;
• optionally substituted aryl refers to an aryl group optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• optionally substituted C6-C10 bicycloalkyl refers to a C6-C10 bicycloalkyl group optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• optionally substituted C3-C8 cycloalkyl refers to a C3-C8 cycloalkyl optionally substituted once with a phenyl, substituted phenyl, hydroxy, or C1-C4 alkoxy;
• optionally substituted heterocycle refers to a heterocycle ring optionally substituted 1 or 2 times independently with a C1-C6 alkyl, halo, benzyl, phenyl, trifluoromethyl, or an oxo group;
• heterocycle refers to stable aromatic and non-aromatic 5- and 6-membered rings containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, said rings being optionally benzofused;
• N-heterocycle refers to a nitrogen containing heterocycle linked through a nitrogen atom;
• optionally substituted N-heterocycle refers to a heterocycle ring, linked through the nitrogen atom, optionally substituted 1 or 2 times independently with a C1-C6 alkyl, halo, benzyl, phenyl, trifluoromethyl, or an oxo group;
• substituted phenoxy refers to a phenoxy group wherein the phenyl is optionally substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• and
• substituted phenyl refers to a phenyl group substituted from 1 to 5 times independently with C1-C6 alkyl, halo, hydroxy, trifluoromethyl, C1-C6 alkoxy, benzyloxy, or trifluoromethoxy;
• in combination with an effective amount of one or more oncolytic agents.