Methods and compounds for inhibitting MRP1

A compound of formula I:

• 32
• where:
• A is a C3-C8 cycloalkyl, optionally substituted 1-3 times with a C1-C4 alkyl;
• het is a five (5) membered heterocyclic ring comprising N and a second heteroatom selected from N, O, or S;
• wherein the non-fused carbon atom of the heteroaryl ring may be optionally substituted with Rb:
• C1-C6 alkyl, optionally substituted aryl, optionally substituted heterocycle, an amino acid ester, CH2OH, CH2O-heterocycle, halo, CH2N3, CH2SR1, CH2NR4R6, OR1, SR13, S(CH2)k-phenyl, or NR4R6;
• provided that when het is pyrazole or imidazole, the saturated nitrogen of the het ring may be optionally substituted with Ra:
• C1-C4 alkyl;
• k is 0, 1, 2, 3, or 4;
• n is 0, 1, or 2;
• p is 0 or 1;
• q is 0, 1, or 2;
• r is 0, 1, or 2;
• t is 0, 1, 2, 3, or 4;
• u is 0, 1, 2, 3, or 4;
• Y is -E-C(O)R3, -E-CH═CHR13, -E-C(OH)R13, -E-NR4R5, -E-OR2, -E-S(O)qR13, -E-SO2NR4R6, —C(R11)=NR6, or an optionally substituted heterocycle;
• E is a bond or —C(R11)(R11)—;
• R1 is independently at each occurrence hydrogen or C1-C6 alkyl;
• R2 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle, C(O)-aryl, or (CH2)2NR4R5;
• R3 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, OR13, or NR4R6;
• R4 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted (C1-C6 alkyl)-aryl, optionally substituted aryl, or R4 and R5, R6, R6′ combine to form ═CR1R14;
• R5 is independently at each occurrence hydrogen, C1-C6 alkyl, C1-C4 alkoxy, optionally substituted heterocycle, optionally substituted C3-Cg 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)R13, C(O)R7, CH2R7, SO2R8, a moiety of the formula
• 33
• or R4 and R5, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R6 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)-heterocyc]e, optionally substituted heterocycle, or R4 and R6, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R6′ 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, (C1-C4 alkyl)-OR13;
• wherein the (C1-C4 alkyl) of the (C1-C4 alkyl)-OR13 may be optionally substituted from 1 to 2 times with C1-C4 alkyl, optionally substituted aryl, optionally substituted heterocycle;
• or R4 and R6′, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R7 is independently at each occurrence optionally substituted C1-C6 alkyl, C1-C6 alkoxy, (C1-C4 alkoxy)-aryl, (C1-C4 alkoxy)-heterocycle, (C1-C4 alkoxy)SiCH3, optionally substituted (C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)-(C3-Cg cycloalkyl), optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C1-C4 alkyl)-CO-aryl, optionally substituted CO-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted CH═CH-heterocycle, optionally substituted phenoxy, optionally substituted heterocycle, optionally substituted (C1-C4 alkyl)-phenoxy, (CH2)tS(O)tR1, (CH2)tC(R12)(R9)N(R16)(R15), (CH2)tC(R12)(R9)O(R17), (CH2)tC(R12)(R9)S(R17), or NR4R6′;
• R8 is independently at each occurrence optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted (C1-C4 alkyl)-heterocycle, or optionally substituted heterocycle;
• R9 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-Cg cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, (CH2)u4C1-C6 alkoxy), optionally substituted (CH2)u—O—(C3-C8 cycloalkyl), optionally substituted (CH2)u—(C1-C4 alkoxy)-aryl, optionally substituted (CH2)u—O-aryl, optionally substituted (CH2)u—O-heterocycle, (C1-C4 alkyl)-CO2—(C1-C6 alkyl), optionally substituted (C1-C4 alkyl)-CO2—(C3-C8 cycloalkyl), optionally substituted (C1-C4 alkyl)CO2—(C1-C4 alkyl)-aryl, optionally substituted (C1-C4 alkyl)-CO2-aryl, optionally substituted (C1-C4 alkyl)-CO2-heterocycle, or R9 and R12 can combine to form a C3-C8 cycloalkyl;
• R10 is 0 to 4 substituents from the aryl ring independently at each occurrence hydrogen, halo, C(O)R3, cyano, optionally substituted heterocycle, optionally substituted aryl, C≡C—R1, C1-C4 alkoxy, (C1-C4 alkyl)-phenyl, NR19R20, or C2-C6 alkenyl;
• R11 is independently at each occurrence hydrogen, C1-C6 alkyl, optionally substituted heterocycle, optionally substituted (C1-C4 alkyl)heterocycle, optionally substituted aryl, or optionally substituted (C1-C4 alkyl)-aryl;
• R12 is independently at each occurrence hydrogen, optionally substituted C1-C6 alky], optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)aryl, optionally substituted aryl, optionally substituted (C1-C4 alkyl)-heterocycle or optionally substituted heterocycle;
• R13 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, Optionally substituted aryl, CO2CH2CO2CH2CH3, or optionally substituted heterocycle;
• R14 is independently at each occurrence C1-C6 alkyl or optionally substituted (C1-C4 alkyl)-aryl;
• R15 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 allyl)-heterocycle, optionally substituted heterocycle, C(O)OR13, SO2R8, C(O)R18, or a moiety of the formula
• 34
• R16 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heterocycle, or —COR8;
• or R16 and R15, together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
• R17 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, COR18, optionally substituted heterocycle, optionally substituted (C1-C4 alkyl)-heterocycle, optionally substituted C1-C6 alkoxy, optionally substituted (C1-C4 alkoxy)-aryl, optionally substituted (C1-C4 alkoxy)-heterocycle, (C1-C4 alkyl)-N(R1)(R1), or an amino acid ester;
• R18 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted (C1-C4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, (C1-C4 alkyl)-NHCO2—(C1-C4 alkyl), or optionally substituted (C1-C4 alkyl)-heterocycle;
• R19 is independently at each occurrence hydrogen, or optionally substituted C1-C6 alkyl;
• R20 is independently at each occurrence hydrogen, optionally substituted C1-C6 alkyl, CH201, CO—(C1-C4 alkyl);
• or a pharmaceutical salt thereof.