PD-1/PD-L1 inhibitors

A compound of formula (VIII):

• wherein:
• each of X4 and X5 are independently N, CH, or CZ3;
• each Z1 is independently halo, —ORa, —NO2, —CN, —NRaRb, —N3, —SO2Ra, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C3-8 cycloalkyl, or —C1-6 alkyl-C3-8 cycloalkyl;
• and
• wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, and cyano;
• each w is independently 0, 1, or 2;
• each Z3 is independently halo, —ORa, —N3, —NO2, —CN, —NR1R2, —SO2Ra, —SO2NRaRb, —NRaSO2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —OC(O)NRaRb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —C3-8 cycloalkyl, —C1-6 alkylC3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, or RN, and
• wherein the alkyl, alkenyl, alkynyl, C3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, cyano, —NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6cyanoalkyl, —C(O)NRaRb, NRaC(O)Ra, —NRaC(O)ORa, —SO2Ra, —NRaSO2Rb, —SO2NRaRb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb, and —C3-8 cycloalkyl;
• RN is independently —C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C1-6 alkylOC1-6 alkylNR1R2, —NRaC1-6 alkylNR1R2, —C1-6 alkylC(O)NR1R2, —O—C1-6 alkylC(O)NR1R2, —O—C1-6 alkylC(O)OR1, —SC1-6 alkylNR1R2, —C1-6 alkylORa, or
• wherein:
• L1 is independently a bond, O, NRa, S, SO, or SO2;
• V is independently selected from a bond, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl;
• wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with ORa, halo, cyano, —NRaRb, or —C3-8 cycloalkyl;
• L2 is independently a bond, O, NRa, S, SO, or SO2;
• ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO2, —N3, —ORa, halo, cyano, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6alkenyl, —C2-6 alkynyl, —O—C1-6 haloalkyl, NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6 alkylCN, —C(O)NRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —C(O)N(Ra)ORb, —SO2Ra, —SO2NRaRb, —NRaSO2Rb, —NRaSO2NRaRb, —C(O)NRaSO2NRaRb, C3-8cycloalkyl, and C1-6alkylC3-8 cycloalkyl;
• and
• wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —ORa, halo, cyano, —NRaRb, or —C3-8 cycloalkyl;
• each t is independently 0, 1, or 2;
• RE and RW are each independently —NR1R2, —C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C1-6 alkylOC1-6alkylNR1R2, —NRa—C1-6 alkylNR1R2, —C1-6 alkylN+R1R2R3, —S—C1-6 alkylNR1R2, —C(O)NR1R2, —SO2Ra, —(CH2)uSO2NR1R2, —(CH2)uNRa—SO2NRaRb, —SO2NRa—C1-6 alkylNR1R2, —NRaSO2—C1-6 alkylNR1R2, —(CH2)uC(O)NRaSO2NRaRb, —(CH2)uN+R1R2O−, —(CH2)uP+RbRcRd, (CH2)uP+RcRdO−, —(CH2)uP+O[NRaRb][NRcRd], —(CH2)uNRcP(O)(ORc)2, —(CH2)uCH2OP(O)(ORc)(ORd), —(CH2)uOP(O)(ORc)(ORd), —(CH2)uOP(O)NRaRb)(ORa), or
• wherein:
• V2 is independently a bond, O, NRa, S, SO, SO2, C(O)NRa, NRaC(O), SO2NR1, or NRaSO2;
• L3 is independently a bond, O, NRa, S, SO, SO2, C(O)NRa, NRaC(O), SO2NR1, or NRaSO2;
• ring B is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• T is independently H, ORa, (CH2)qNR1R2, (CH2)qNRaC(O)Re, or (CH2)qC(O)Re;
• p is independently 0, 1, 2, 3, 4, or 5;
• q is independently 0, 1, 2, 3, 4, or 5;
• u is 0, 1, 2, 3, or 4;
• z is 0, 1, 2, or 3;
• and
• wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of RE or RW is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NRaRb, halo, cyano, oxo, ORa, —C1-6 alkyl, —C1-6 haloalkyl, —C1-6 cyanoalkyl, —C1-6 alkylNRaRb, —C1-6 alkylOH, —C3-8 cycloalkyl, and —C1-3 alkylC3-8cycloalkyl;
• provided that at least one of V2, L3, ring B, and T contains a nitrogen atom;
• each R1 is independently selected from H, —C1-8 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C1-6 alkylC(O)ORa, —C2-6 alkenylC(O)ORa, —SO2Ra, —SO2NRaRb, —C(O)NRaSO2Ra, and C1-6 alkylC3-8cycloalkyl;
• wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —ORa, —CN, halo, C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —OC(O)NRaRb, NRaC(O)ORb, —C1-6 alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, —C1-6 alkylSO2NRaRb, —C(O)NRaSO2Rb, —C1-6 alkylC(O)NRaSO2Rb, —NRaC(O)Rb, and —C1-6alkylNRaC(O)Rb;
• each R2 is independently selected from H, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, and —C2-6 alkenylC(O)ORa;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —ORa, —CN, halo, C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, —C1-6 alkylSO2NRaRb, —C(O)NRaSO2Rb, and —NRaC(O)Rb;
• or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally substituted with 1 to 3 groups independently selected from oxo, —C1-6 alkyl, —C3-8 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —ORa, —C(O)ORa, —C1-6 cyanoalkyl, —C1-6 alkylORa, —C1-6 haloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, C1-6 alkylC(O)Ra, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —SO2Ra, —C1-6 alkylSO2Ra, —SO2NRaRb, and C1-6 alkylSO2NRaRb;
• each R3 is independently H, —C1-6 alkyl, —C2-6 alkenyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, or —C2-6 alkenylC(O)ORa;
• each Ra is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6alkylheterocyclyl;
• each Rb is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• or Ra and Rb may combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S;
• wherein the ring is optionally substituted with 1 to 4 groups independently selected from —ORf, —CN, halo, —C1-6 alkylORf, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Rf, —C1-6 alkylC(O)Rf, —C(O)ORf, —C1-6 alkylC(O)ORf, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —SO2Rf, —C1-6 alkylSO2Rf, —SO2NRfRg, —C1-6 alkylSO2NRfRg, —C(O)NRfSO2Rg, and —NRfC(O)Rg;
• each Rc is independently selected from H, OH, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• Rd is independently selected from H, —C1-6 alkyl, —C3-C8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• each Re is independently selected from H, —C1-6 alkyl, —O—C1-6alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C3-8 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6alkylheteroaryl, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —NHSO2Rf, —C1-6 alkylSO2Rf, and —C1-6 alkylSO2NRfRg;
• each Rf is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• and
• each Rg is independently selected from H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• or a pharmaceutically acceptable salt thereof.