Combination therapy

A method for treating a non-Hodgkin's lymphoma, non-small cell lung cancer, melanoma, renal cell cancer, head and neck cancer, colon cancer, mesothelioma, comprising administering:

• (i) an effective amount of a compound of Formula (I);
• or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof;
• or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• X, Y, and Z are each independently N or CRx, with the proviso that at least two of X, Y, and Z are nitrogen atoms;
• where RX is hydrogen or C1-6 alkyl;
• R1 and R2 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;
• wherein each R1a, R1b, R1c, and R1d is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) R1b and R1c together with the N atom to which they are attached form heterocyclyl;
• R3 and R4 are each independently hydrogen or C1-6 alkyl;
• or R3 and R4 are linked together to form a bond, C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene;
• R5a is (a) hydrogen or halo;
• (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;
• R5b is (a) halo;
• (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;
• R5c is —(CR5fR5g)n—(C6-14 aryl) or —(CR5fR5g)n-heteroaryl;
• R5d and R5e are each independently (a) hydrogen or halo;
• (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;
• R5f and R5g are each independently (a) hydrogen or halo;
• (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;
• or (d) when one occurrence of R5f and one occurrence of R5g are attached to the same carbon atom, the R5f and R5g together with the carbon atom to which they are attached form a C3-10 cycloalkyl or heterocyclyl;
• R6 is hydrogen, C1-6 alkyl, —S—C1-6 alkyl, —S(O)—C1-6 alkyl, or —SO2—C1-6 alkyl;
• m is 0 or 1;
• and
• n is 0, 1, 2, 3, or 4;
• wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R1, R2, R3, R4, R6, RX, R1a, R1b, R1c, R1d, R5a, R5b, R5c, R5d, R5e, R5f, and R5g is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro;
• (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one, two, three, or four 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, —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, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four substituents Qa;
• or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with 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, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
• and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(NRe)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(═NRe)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORh, —NReC(O)NRfRg, —NReC(═NRh)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
• wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen;
• (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
• or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl;
• or
• wherein two substituents Q that are adjacent to each other optionally form a C3-10 cycloalkenyl, C6-14 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four substituents Qa;
• and
• (ii) an effective amount of a PD-1 or PD-L1 inhibitor.