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

A compound of Formula I:

• 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;
• R1 is (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;
• (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)NR1bR1c, —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;
• or (d) —C(O)CR1e═CR1fCR1g,
• —N1aC(O)CR1e═CR1fCR1g,
• —S(O)CR1e═CR1fCR1g,
• —S(O2)CR1e═CR1fCR1g,
• —NR1aS(O)CR1e═CR1fCR1g,
• —NR1aS(O2)CR1e═CR1fCR1g, or
• 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;
• T is a bond, —O—, —S—, —N═, —N(R4)—, or —C(R4)═;
• U is a bond, —O—, —S—, —N═, —N(R5)—, or —C(R5)═;
• V is a bond, —O—, —S—, —N═, —N(R6)—, or —C(R6)═;
• W is a bond, —O—, —S—, —N═, —N(R7)—, or —C(R7)═;
• X and Y are each independently C or N;
• 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)NR1bR1c, —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;
• with proviso that at least two of R4, R5, R6, and R7 are not hydrogen;
• and with the proviso that R4 and R5, R5 and R6, or R6 and R7 are linked together to form heteroaryl or heterocyclyl;
• each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, R1c, 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;
• and
• each R1e, R1f, and R1g 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;
• with the proviso that no more than one of T, U, V, and W is a bond;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, 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, in one embodiment, one, two, three, or four, substituents Qa;
• and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —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(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —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, in one embodiment, one, two, three, or four, 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, in one embodiment, one, two, three, or four, 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, —ORf, —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.