PD-1/PD-L1 inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is N, CH, or CZ3;
• X2 is N, CH, or CZ3;
• Y1 is O, NH, or CH2 and the dashed lines are single bonds, or Y1 is halo or —C1-6 alkyl and the dashed lines are absent;
• ring B is
• w is 0, 1, or 2;
• each Z1 is independently halo, —ORa, —NO2, cyano, —NRaRb, —N3, —S(O)2Ra, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —O—C1-6haloalkyl, —C3-8 cycloalkyl, or —C1-6 alkylC3-8 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;
• x is 0, 1, or 2;
• each Z2 is independently halo, —ORa, —NO2, cyano, —NRaRb, —N3, —S(O)2Ra, —C1-6 alkyl, —C1-6 haloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C3-8 cycloalkyl, or —C1-6 alkylC3-8 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;
• t is 0, 1, or 2;
• each Z3 is independently halo, —ORa, —N3, —NO2, cyano, —NR1R2, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Ra, —NRaC(O)Ra, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRaC(O)ORa, —NRaC(O)NR1R2, —OC(O)NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 alkyl, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —O—C1-6 cyanoalkyl, —O—C1-6 haloalkyl, —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—C1-6 cyanoalkyl, —C(O)NRaRb,
• NRaC(O)Ra, —NRaC(O)ORa, —S(O)2Ra, —NRaS(O)2Rb, —S(O)2NRaRb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, and —C3-8 cycloalkyl;
• RN is independently —C1-6 alkylNR1R2, —OC1-6 alkylNR1R2, —C1-6 alkyl-O—C1-6 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—, —S(O)—, or —S(O)2—;
• V is independently selected from a bond, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• 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—, —S(O)—, or —S(O)2—;
• 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, —C2-6 alkenyl, —C2-6 alkynyl, —O—C1-6 haloalkyl, —NRaRb, —C(O)Ra, —C(O)ORa, —O—C1-6 cyanoalkyl, —C(O)NRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —C(O)N(Ra)ORb, —S(O)2Ra, —S(O)2NRaRb, —NRaS(O)2Rb, —NRaS(O)2NRaRb, —C(O)NRaS(O)2NRaRb, —C3-8 cycloalkyl, and —C1-6 alkylC3-8 cycloalkyl;
• and
• wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —ORa, halo, cyano, —NRaRb, or —C3-8 cycloalkyl;
• RE is hydrogen, halo, —OH, —NR1C(O)NR1R2, —C1-6 alkylOC(O)NR1R2, —C1-6 alkylNR1C(O)R2, —CN, —C1-9 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C1-8 haloalkyl, C1-8 alkoxy, or C3-15 cycloalkyl;
• RW is —NR1R2, —C1-6 alkylNR1R2, —O—C1-6 alkylNR1R2, —C1-6alkyl-O—C1-6 alkylNR1R2, —NRa—C1-6alkylNR1R2, —C1-6 alkylN+R1R2R3, —S—C1-6 alkylNR1R2, —C(O)NR1R2, —S(O)2Ra, —(CH2)uS(O)2NR1R2, —(CH2)uNRaS(O)2NRaRb, —S(O)2NRaC1-6alkylNR1R2, —NRaS(O)2C1-6alkylNR1R2, —(CH2)uC(O)NRaS(O)2NRaRb, —(CH2)+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—, —S(O)—, —S(O)2—, —C(O)NRa—, —NRaC(O)—, —S(O)2NR1—, or —NRaS(O)2—;
• L3 is independently a bond, —O—, —NRa—, —S—, —S(O)—, —S(O)2—, —C(O)NRa—, —NRaC(O)—, —S(O)2NR1—, or —NRaS(O)2—;
• ring B′ is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• T is independently hydrogen, —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, —C1-6haloalkyl, —C1-6 cyanoalkyl, —C1-6 alkylNRaRb, —C1-6hydroxyalkyl, —C3-8 cycloalkyl, and —C1-3 alkylC3-8 cycloalkyl;
• provided that at least one of V2, L3, ring B′, and T contains a nitrogen atom;
• each R1 is independently selected from hydrogen, —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, —S(O)2Ra, —S(O)2NRaRb, —C(O)NRaS(O)2Ra, and —C1-6 alkylC3-8 cycloalkyl;
• wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —ORa, cyano, halo, C1-6 alkyl, —C1-6alkylORa, —C1-6cyanoalkyl, —C1-6haloalkyl, C3-8cycloalkyl, —C1-3 alkylC3-8 cycloalkyl, —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, —C1-6alkylC(O)NRaRb, —S(O)2Ra, —C1-6alkylS(O)2Ra, —S(O)2NRaRb, —C1-6 alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb, —C1-6 alkylC(O)NRaS(O)2Rb, —NRaC(O)Rb, and —C1-6 alkylNRaC(O)Rb;
• each R2 is independently selected from hydrogen, —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, cyano, halo, —C1-6 alkyl, —C1-6alkylORa, —C1-6cyanoalkyl, —C1-6haloalkyl, —C3-8cycloalkyl, —C1-3 alkylC3-8 cycloalkyl, —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, —S(O)2Ra, —C1-6alkylS(O)2Ra, —S(O)2NRaRb, —C1-6alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb, and —NRaC(O)Rb;
• or R1 and R2 combine to form a heterocyclyl 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, —C1-6cyanoalkyl, —C1-6 alkylORa, —C1-6haloalkyl, —C1-3 alkylC3-8 cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —S(O)2Ra, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, —C(O)N═S(O)RaNRaRb, —C(O)N═S(O)RaNRaC(O)Rb, and —C1-6 alkylS(O)2NRaRb;
• each R3 is independently hydrogen, —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 hydrogen, —C1-6 alkyl, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• each Rb is independently selected from hydrogen, —C1-6 alkyl, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• or Ra and Rb may combine together to form a heterocyclyl optionally substituted with 1 to 4 groups independently selected from —ORf, cyano, halo, —C1-6 alkylORf, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8 cycloalkyl, —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, —S(O)2Rf, —C1-6alkylS(O)2Rf, —S(O)2NRfRg, —C1-6alkylS(O)2NRfRg, —C(O)NRfS(O)2Rg, and —NRfC(O)Rg;
• each Rc is independently selected from hydrogen, —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;
• each Rd is independently selected from hydrogen, —C1-6 alkyl, —C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
• each Re is independently selected from hydrogen, —C1-6 alkyl, —O—C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C3-8 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —NHS(O)2Rf, —C1-6 alkylS(O)2Rf, and —C1-6 alkyl S(O)2NRfRg;
• each Rf is independently selected from hydrogen, —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 hydrogen, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl.