PD-1/PD-L1 inhibitors
Compounds and methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH, CZ 3 , or N;
each Z 1 is independently halo, —OR a , —SR a , —NO 2 , —CN, —NR a R b , —N 3 , —S(O) 2 R a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —C 3-8 cycloalkyl or —C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;
each Z 3 is independently halo, oxo, —OR a , N 3 , NO 2 , —CN, —NR 1 R 2 , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R a , —NR a C(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)OR a , —NR a C(O)NR 1 R 2 , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —C 3-8 cycloalkyl, —C 1-6 alkylC 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and R N ;
wherein the alkyl, alkenyl, alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , N 3 , —OR a , halo, cyano, —NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 alkylCN, —CONR a R b , NR a COR a , —NR a C(O)OR a , —S(O) 2 R a , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b and —C 3-8 cycloalkyl;
each R N is independently —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)OR 1 , —S—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or
wherein
L 1 is independently a bond, O, NR a , S, S(O), or S(O) 2 ;
V is independently selected from the group consisting of a bond, C 1-6 alkyl,
C 2-6 alkenyl, and C 2-6 alkynyl;
L 2 is independently a bond, O, NR a , S, S(O), or S(O) 2 ;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and —C 3-8 cycloalkyl;
ring A is cycloalkyl, aryl, heteroaryl, or heterocyclyl;
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , N 3 , —OR a , halo, cyano, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 haloalkyl, NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 alkylCN, —CONR a R b , —NR a COR a , —NR a C(O)OR a , —NR a C(O)OR a , —C(O)N(R a )OR b , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , C 3-8 cycloalkyl and C 1-6 alkylC 3-8 cycloalkyl;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and —C 3-8 cycloalkyl;
R E and R W are each independently —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —C 1-6 alkylNR a C 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylN + R 1 R 2 R 3 , —S—C 1-6 alkylNR 1 R 2 , —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —S(O) 2 R a , —(CH 2 ) u S(O) 2 NR 1 R 2 , —(CH 2 ) u NR a S(O) 2 NR a R b , —(CH 2 ) u NR a N(R a )NR a R b , —(CH 2 ) u C(O)NR 1 R 2 , —S(O) 2 NR a C 1-6 alkylNR 1 R 2 , —NR a S(O) 2 C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a S(O) 2 NR a R b , —(CH 2 ) u N + R 1 R 2 O − , —(CH 2 ) u P + R b R c R d , —(CH 2 ) u P + R c R d O − , —(CH 2 ) u P + O[NR a R b ][NR c R d ], —(CH 2 ) u NR c P(O)(OR c ) 2 , —(CH 2 ) u CH 2 OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(NR a R b )(OR a ), or
wherein:
V 2 is independently a bond, O, NR a , S, S(O), S(O) 2 , C(O)NR a , NR a C(O), S(O) 2 NR 1 , or NR a S(O) 2 ;
L 3 is independently a bond, O, NR a , S, S(O), S(O) 2 , C(O)NR a , NR a C(O), S(O) 2 NR 1 , or NR a S(O) 2 ;
ring B is cycloalkyl, aryl, heteroaryl or heterocyclyl;
T is independently H, —OR a , (CH 2 ) q NR 1 R 2 , (CH 2 ) q S(O) 2 R e , (CH 2 ) q NR a C(O)R e , or (CH 2 ) q C(O)R e ;
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 R E or R W is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NR a R b , halo, cyano, oxo, —OR a , —C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 haloalkyl, —C 1-6 cyanoalkyl, —C 1-6 alkylNR a R b , —C 1-6 alkylOH, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl and —C 1-6 alkylheterocyclylCN;
provided that at least one of V 2 , L 3 , ring B and T contains a nitrogen atom;
each R 1 is independently selected from the group consisting of H, —C 1-8 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 1-6 alkylC(O)OR a , —C 2-6 alkenylC(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —CONR a S(O) 2 R a , and C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —OR a , —CN, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, C 3-8 cycloalkyl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —O—C 1-6 alkylC(O)NR a R b , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —OC(O)NR a R b , —NR a C(O)OR b , —NR a C(O)NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , —C 1-6 alkylC(O)NR a S(O) 2 R b , —NR a C(O)R b , and —C 1-6 alkylNR a C(O)R b ;
each R 2 is independently selected from the group consisting of H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , and —C 2-6 alkenylC(O)OR a ;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —OR a , —CN, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —CONR a R b , C 1-6 alkylCONR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —CONR a S(O) 2 R b and —NR a C(O)R b ;
or R 1 and R 2 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 the group consisting of halo, oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, heteroaryl, heterocyclyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —CONR a R b , —C 1-6 alkylCONR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , and —C 1-6 alkylS(O) 2 NR a R b ;
each R 3 is independently H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , or —C 2-6 alkenylC(O)OR a ;
each R a is independently selected from the group consisting of H, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;
each R b is independently selected from the group consisting of H, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;
or R a and R b 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 the group consisting of —OR f , —CN, halo, —C 1-6 alkylOR f , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R f , —C 1-6 alkylC(O)R f , —C(O)OR f , —C 1-6 alkylC(O)OR f , —NR f R g , —C 1-6 alkylNR f R g , —CONR f R g , C 1-6 alkylCONR f R g , —S(O) 2 R f , —C 1-6 alkylS(O) 2 R f , —S(O) 2 NR f R g , —C 1-6 alkylS(O) 2 NR f R g , —CONR f S(O) 2 R g , and —NR f COR g ;
each R c is independently selected from the group consisting of H, OH, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl; and
each R d is independently selected from the group consisting of H, —C 1-6 alkyl, —C 1-3 , —C 8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;
each R e is independently selected from the group consisting of H, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C 3-8 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C 1-3 alkylC 3-8 cyclo alkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —NHS(O) 2 R f , —C 1-6 alkylS(O) 2 R f , and —C 1-6 alkylS(O) 2 NR f R g ;
each R f is independently selected from the group consisting of H, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl; and
each R g is independently selected from the group consisting of H, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl.
2. A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH, CZ 3 , or N;
each Z 1 is independently halo, —OR a , —NO 2 , —CN, —NR a R b , —N 3 , —S(O) 2 R a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, monocyclic —C 3-8 cycloalkyl, or monocyclic —C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;
each Z 3 is independently halo, oxo, —OR a , N 3 , NO 2 , —CN, —NR 1 R 2 , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R a , —NR a C(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)OR a , —NR a C(O)NR 1 R 2 , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic —C 1-6 alkylC 3-8 cycloalkyl, monocyclic aryl, or R N ;
wherein the alkyl, alkenyl, alkynyl, monocyclic C 3-8 cycloalkyl, or monocyclic aryl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , N 3 , —OR a , halo, cyano, —NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 alkylCN, —CONR a R b , NR a COR a , —NR a C(O)OR a , —S(O) 2 R a , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b and monocyclic —C 3-8 cycloalkyl;
each R N is independently —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)OR 1 , —S—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or
wherein
L 1 is independently a bond, O, NR a , S, S(O), or S(O) 2 ;
V is independently selected from the group consisting of a bond, C 1-6 alkyl,
C 2-6 alkenyl, and C 2-6 alkynyl;
L 2 is independently a bond, O, NR a , S, S(O), or S(O) 2 ;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and monocyclic —C 3-8 cycloalkyl;
ring A is monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl;
wherein the monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , N 3 , —OR a , halo, cyano, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 haloalkyl, NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 alkylCN, —CONR a R b , —NR a COR a , —NR a C(O)OR a , —NR a C(O)OR a , —C(O)N(R a )OR b , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , monocyclic C 3-8 cycloalkyl and monocyclic C 1-6 alkylC 3-8 cycloalkyl;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and monocyclic —C 3-8 cycloalkyl;
R E and R W are each independently —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —NR a C 1-6 alkylNR 1 R 2 , —C 1-6 alkylN + R 1 R 2 R 3 , —SC 1-6 alkylNR 1 R 2 , C(O)NR 1 R 2 , —S(O) 2 R a , —(CH 2 ) u S(O) 2 NR 1 R 2 , —(CH 2 ) u NR a S(O) 2 NR a R b , —S(O) 2 NR a C 1-6 alkylNR 1 R 2 , —NR a S(O) 2 C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a S(O) 2 NR a R b , —(CH 2 ) u N + R 1 R 2 O − , —(CH 2 ) u P + R b R c R d , —(CH 2 ) u P + R c R d O − , —(CH 2 ) u P + O[NR a R b ][NR c R d ], —(CH 2 ) u NR c P(O)(OR c ) 2 , —(CH 2 ) u CH 2 OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(NR a R b )(OR a ), or
wherein:
V 2 is independently a bond, O, NR a , S, S(O), S(O) 2 , C(O)NR a , NR a C(O), S(O) 2 NR 1 , or NR a S(O) 2 ;
L 3 is independently a bond, O, NR a , S, S(O), S(O) 2 , C(O)NR a , NR a C(O), S(O) 2 NR 1 , or NR a S(O) 2 ;
ring B is monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, or spirocyclic heterocyclyl;
T is independently H, —OR a , (CH 2 ) q NR 1 R 2 , (CH 2 ) q NR a C(O)R c , or (CH 2 ) q C(O)R e ;
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, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl or spirocyclic heterocyclyl of R E or R W is optionally substituted with 1 to 3 substituents independently selected from the group consisting of NR a R b , halo, cyano, oxo, —OR a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 cyanoalkyl, —C 1-6 alkylNR a R b , —C 1-6 alkylOH, monocyclic —C 3-8 cycloalkyl and monocyclic —C 1-3 alkylC 3-8 cycloalkyl;
provided that at least one of V 2 , L 3 , ring B and T contains a nitrogen atom;
each R 1 is independently selected from the group consisting of H, —C 1-8 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, monocyclic —C 3-6 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, monocyclic —C 1-6 alkylheterocyclyl, —C 1-6 alkylC(O)OR a , —C 2-6 alkenylC(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —CONR a S(O) 2 R a , and monocyclic C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —OR a , —CN, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, monocyclic C 3-8 cycloalkyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkyl C(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —OC(O)NR a R b , NR a C(O)OR b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , —C 1-6 alkylC(O)NR a S(O) 2 R b , —NR a C(O)R b , and —C 1-6 alkylNR a C(O)R b ;
each R 2 is independently selected from the group consisting of H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, monocyclic —C 3-6 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, monocyclic —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , and —C 2-6 alkenylC(O)OR a ;
wherein each alkyl, alkenyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —OR a , —CN, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, monocyclic —C 3-8 cycloalkyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —CONR a R b , C 1-6 alkylCONR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —CONR a S(O) 2 R b , and —NR a C(O)R b ;
or R 1 and R 2 , when bound to the same atom, may combine with the atom to which they are attached to form a monocyclic 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 the group consisting of oxo, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —CONR a R b , —C 1-6 alkylCONR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , and C 1-6 alkylS(O) 2 NR a R b ;
each R 3 is independently H, —C 1-6 alkyl, —C 2-6 alkenyl, monocyclic —C 3-6 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, monocyclic —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , or —C 2-6 alkenylC(O)OR a ;
each R a is independently selected from the group consisting of H, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl;
each R b is independently selected from the group consisting of H, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl;
or R a and R b , when bound to the same atom, may combine together to form a monocyclic 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 the group consisting of —OR f , —CN, halo, —C 1-6 alkylOR f , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, monocyclic —C 3-8 cycloalkyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R f , —C 1-6 alkylC(O)R f , —C(O)OR f , —C 1-6 alkylC(O)OR f , —NR f R g , —C 1-6 alkylNR f R g , —CONR f R g , C 1-6 alkylCONR f R g , —S(O) 2 R f , —C 1-6 alkylS(O) 2 R f , —S(O) 2 NR f R g , —C 1-6 alkylS(O) 2 NR f R g , —CONR f S(O) 2 R g , and —NR f COR g ;
each R c is independently selected from the group consisting of H, OH, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl; and
each R d is independently selected from the group consisting of H, —C 1-6 alkyl, monocyclic —C 3 —C 8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl;
each R e is independently selected from the group consisting of H, —C 1-6 alkyl, —O—C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —O—C 3-8 cycloalkyl, monocyclic —O-aryl, monocyclic —O-heteroaryl, monocyclic —O-heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —NHS(O) 2 R f , —C 1-6 alkylS(O) 2 R f , and —C 1-6 alkylS(O) 2 NR f R g ;
each R f is independently selected from the group consisting of H, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl; and
each R g is independently selected from the group consisting of H, —C 1-6 alkyl, monocyclic —C 3-8 cycloalkyl, monocyclic aryl, monocyclic heteroaryl, monocyclic heterocyclyl, monocyclic —C 1-3 alkylC 3-8 cycloalkyl, monocyclic —C 1-6 alkylaryl, monocyclic —C 1-6 alkylheteroaryl, and monocyclic —C 1-6 alkylheterocyclyl.
3. The compound of claim 1 , represented by Formula (IIa):
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , represented by Formula (IIb):
or a pharmaceutically acceptable salt thereof.
5. A compound selected from:
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 6 , further comprising at least one additional anticancer agent or therapy selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab, and at least one pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 6 , further comprising at least one additional anticancer agent or therapy selected from nivolumab, pembrolizumab, atezolizumab, and ipilimumab.
9. A method for inhibiting Programmed death-1 (PD-1), Programmed death-ligand 1 (PD-L1) and/or the PD-1/PD-L1 interaction comprising administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof, to a patient in need thereof.