PD-1/PD-L1 inhibitors
Compounds according to formula (I), 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 (VIII):
wherein:
each of X 4 and X 5 are independently N, CH, or CZ 3 ;
each Z 1 is independently halo, —OR a , —NO 2 , —CN, —NR a R b , —N 3 , —SO 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 alkyl-C 3-8 cycloalkyl; and
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;
each w is independently 0, 1, or 2;
each Z 3 is independently halo, —OR a , —N 3 , —NO 2 , —CN, —NR 1 R 2 , —SO 2 R a , —SO 2 NR a R b , —NR a SO 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 SO 2 NR a R b , —C(O)NR a SO 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, or RN, and
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 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 cyanoalkyl, —C(O)NR a R b , NR a C(O)R a , —NR a C(O)OR a , —SO 2 R a , —NR a SO 2 R b , —SO 2 NR a R b , —NR a SO 2 NR a R b , —C(O)NR a SO 2 NR a R b , and —C 3-8 cycloalkyl;
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 , —SC 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or
wherein: L 1 is independently a bond, O, NR a , S, SO, or SO 2 ;
V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;
L 2 is independently a bond, O, NR a , S, SO, or SO 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, —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, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —C(O)N(R a )OR b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R b , —NR a SO 2 NR a R b , —C(O)NR a SO 2 NR a R b , C 3-8 cycloalkyl, and C 1-6 alkylC 3-8 cycloalkyl; and
wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;
each t is independently 0, 1, or 2;
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 , —S—C 1-6 alkylNR 1 R 2 , —C(O)NR 1 R 2 , —SO 2 R a , —(CH 2 ) u SO 2 NR 1 R 2 , —(CH 2 ) u NR a —SO 2 NR a R b , —SO 2 NR a —C 1-6 alkylNR 1 R 2 , —NR a SO 2 —C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a SO 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, SO, SO 2 , C(O)NR a , NR a C(O), SO 2 NR 1 , or NR a SO 2 ;
L 3 is independently a bond, O, NR a , S, SO, SO 2 , C(O)NR a , NR a C(O), SO 2 NR 1 , or NR a SO 2 ;
ring B is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;
T is independently H, OR a , (CH 2 ) q NR 1 R 2 , (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 1-6 haloalkyl, —C 1-6 cyanoalkyl, —C 1-6 alkylNR a R b , —C 1-6 alkylOH, —C 3-8 cycloalkyl, and —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 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 , —SO 2 R a , —SO 2 NR a R b , —C(O)NR a SO 2 R a , and C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —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 , —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 , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , —C 1-6 alkylSO 2 NR a R b , —C(O)NR a SO 2 R b , —C 1-6 alkylC(O)NR a SO 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 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, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —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 , —C(O)NR a R b , C 1-6 alkylC(O)NR a R b , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , —C 1-6 alkylSO 2 NR a R b , —C(O)NR a SO 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 oxo, —C 1-6 alkyl, —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, —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 , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , and C 1-6 alkylSO 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 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;
each R b is independently selected from 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;
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 —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 , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —SO 2 R f , —C 1-6 alkylSO 2 R f , —SO 2 NR f R g , —C 1-6 alkylSO 2 NR f R g , —C(O)NR f SO 2 R g , and —NR f C(O)R g ;
each R c is independently selected from 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;
R d is independently selected from H, —C 1-6 alkyl, —C 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 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 cycloalkyl, —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 , —NHSO 2 R f , —C 1-6 alkylSO 2 R f , and —C 1-6 alkylSO 2 NR f R g ;
each R f is independently selected from 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 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;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIa):
3 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIe):
wherein:
each of X 4 and X 5 are independently N, CH, or CZ 3 ;
each Z 1 is independently halo, —OR a , —CN, or —C 1-6 alkyl;
each w is independently 0, 1, or 2;
each Z 3 is independently halo, —OR a , —N 3 , —NO 2 , —CN, —NR 1 R 2 , —SO 2 R a , —SO 2 NR a R b , —NR a SO 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 SO 2 NR a R b , —C(O)NR a SO 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, or R N , and
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 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 cyanoalkyl, —C(O)NR a R b , NR a C(O)R a , —NR a C(O)OR a , —SO 2 R a , —NR a SO 2 R b , —SO 2 NR a R b , —NR a SO 2 NR a R b , —C(O)NR a SO 2 NR a R b , and —C 3-8 cycloalkyl;
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, SO, or SO 2 ;
V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;
L 2 is independently a bond, O, NR a , S, SO, or SO 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, —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, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —C(O)N(R a )OR b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R b , —NR a SO 2 NR a R b , —C(O)NR a SO 2 NR a R b , C 3-8 cycloalkyl, and C 1-6 alkylC 3-8 cycloalkyl; and
wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR a , halo, cyano, —NR a R b or —C 3-8 cycloalkyl;
each t is independently 0, 1, or 2;
each R 1 is independently selected from 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 , —SO 2 R a , —SO 2 NR a R b , —C(O)NR a SO 2 R a , and C 1-6 alkylC 3-8 cycloalkyl;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —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 , —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 , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , —C 1-6 alkylSO 2 NR a R b , —C(O)NR a SO 2 R b , —C 1-6 alkylC(O)NR a SO 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 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, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —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 , —C(O)NR a R b , C 1-6 alkylC(O)NR a R b , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , —C 1-6 alkylSO 2 NR a R b , —C(O)NR a SO 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 oxo, —C 1-6 alkyl, —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, —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 , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —SO 2 R a , —C 1-6 alkylSO 2 R a , —SO 2 NR a R b , and C 1-6 alkylSO 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 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;
each R b is independently selected from 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;
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 —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 , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —SO 2 R f , —C 1-6 alkylSO 2 R f , —SO 2 NR f R g , —C 1-6 alkylSO 2 NR f R g , —C(O)NR f SO 2 R g , and —NR f C(O)R g ;
each R c is independently selected from 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;
each R d is independently selected from H, —C 1-6 alkyl, —C 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 f is independently selected from 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 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;
or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 3 , wherein the compound is represented by a compound of formula (VIIIf):
5 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIg):
6 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIh):
7 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIi):
8 . The compound of claim 1 , wherein each Z 1 is independently halo.
9 . The compound of claim 1 , wherein each Z 3 is independently halo or C 1-6 alkoxy.
10 . The compound according to claim 1 , wherein R E and R W are independently selected from —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , —OC 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 , —SO 2 R a , —(CH 2 ) u SO 2 NR 1 R 2 , —(CH 2 ) u NR a SO 2 NR a R b , —SO 2 NR a C 1-6 alkylNR 1 R 2 , —NR a SO 2 C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a SO 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 ), and —(CH 2 ) u OP(O)NR a R b )(OR a );
R 1 is H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , or —C 1-6 alkylC(O)OR a ;
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from —OR a , —CN, halo, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-3 haloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —C(O)NR a R b , and —C 1-6 alkylC(O)NR a R b ;
R 2 is selected from —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , and —C 1-6 alkylC(O)OR a ;
wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from —OR a , —CN, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-3 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 3 , —C 1-6 alkylC(O)OR a , —C(O)NR a R b , and C 1-6 alkylC(O)NR a R b ,
or R 1 and R 2 combine to form a heterocyclyl optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen, and optionally substituted with 1 to 3 groups independently selected from oxo, —C 1-6 alkyl, —OR a , —C(O)OR a , —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 , and —C(O)NR a R b ;
R 3 is independently H, —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, or —C 1-6 alkylaryl;
R a is independently H or —C 1-6 alkyl;
R b is independently H or —C 1-6 alkyl;
R c is independently selected from H, —C 1-6 alkyl, —C 3-8 cycloalkyl, and —C 1-3 alkylC 3-8 cycloalkyl;
R d is independently selected from H, —C 1-6 alkyl, —C 3 -C 8 cycloalkyl, and —C 1-3 alkylC 3-8 cycloalkyl; and
u is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
11 . The compound according to claim 1 , wherein the groups R E and R W are each independently:
12 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
14 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
15 . A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
16 . The pharmaceutical composition according to claim 15 , further comprising at least one additional anticancer agent or therapy.
17 . The pharmaceutical composition according to claim 15 , 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.
18 . A method for inhibiting PD-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.