Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer

A method for treating or ameliorating one or more symptoms of an EGFR-mediated proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula IV:

• or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof;
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
• wherein:
• R1 is:
• R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• L1 is a bond, —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R1B is independently hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• L2 is C3-10 cycloalkylene, C6-14 arylene, C7-15 aralkylene, heteroarylene, or heterocyclylene;
• Z is NR2A or CR2AR2B, wherein each R2A and R2B is independently hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• R4, R5, R6, and R7 are each independently (a) hydrogen, cyano, halo, or nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)N1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
• and
• each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl;
• or R1b and R1c together with the N atom to which they are attached form heterocyclyl;
• with the proviso that, when L1 is a bond, at least one of R4, R5, R6, and R7 is bromo, —OR7a, or —NR1bR1c, wherein R7a is C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Qa;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OP(O)(ORa)2, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRa)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa;
• or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Qa;
• wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Rf, —C(O)ORf, —C(O)NRgRh, —C(NRf)NRgRh, —OC(O)Rf, —OC(O)ORf, —OC(O)NRgRh, —OC(═NRf)NRgRh, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRgRh, —OS(O)2NRgRh, —NRgRh, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRgRh, —NRfC(═NRk)NRgRh, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRgRh, —NRfS(O)2NRgRh, —SRf, —S(O)Rf, —S(O)2Rf, —S(O)NRgRh, and —S(O)2NRgRh;
• wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.