IP Library › Patent Application 15957739

Patent Application

App. No. 15/957,739

PD-1/PD-L1 INHIBITORS

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App. No.: 15/957,739

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Abstract

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.

Claims (441)

1 . A compound of formula (VIII):

wherein:

each of X 4 and X 5 are independently N, CH or CZ 3 ;

each Z is independently is 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, and 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; and further wherein the heteroaryl or heterocyclic group may be oxidized on a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to form a sulfoxide or sulfone;

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 , —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 )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, stereoisomer, mixture of stereoisomers, solvate, or tautomer 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 (VIIIb):

4 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIc):

5 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIId):

6 . 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;

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 ,

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 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;

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 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;

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof.

7 . The compound of claim 6 , wherein the compound is represented by a compound of formula (VIIIf):

8 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIg):

9 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIh):

10 . The compound of claim 1 , wherein the compound is represented by a compound of formula (VIIIi):

11 . The compound of any preceding claim, wherein each Z 3 is independently halo.

12 . The compound of any preceding claim, wherein each Z 3 is independently halo or C 1-6 alkoxy.

13 . The compound of any preceding claim, wherein each Z 3 is independently chloro.

14 . The compound of any preceding claim, wherein each Z 3 is independently chloro or methoxy.

15 . A compound of formula (I)

R W -Q W -L W -Ar W —Ar E -L E -Q E -R E (I)

wherein:

Ar E and Ar W are each independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from 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, —OC 1-6 alkyl, —OC 1-6 haloalkyl, —C 3-8 cycloalkyl, and —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 oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

L E and L W are each independently a bond, —O—, —S—, —SO—, —SO 2 —, —(CR 3 R 4 ) m —, —(CR 3 R 4 ) m O(CR 3 R 4 ) m —, —(CR 3 R 4 ) m S(CR 3 R 4 ) m —, —(CR 3 R 4 ) m NR 3 (CR 3 R 4 ) m —, —C(O)—, —(CR 3 R 4 ) m C(O)(CR 3 R 4 ) m —, —(CR 3 R 4 ) m C(O)NR 3 (CR 3 R 4 ) m —, —(CR 3 R 4 ) m NR 3 C(O)(CR 3 R 4 ) m —, C 2-6 alkenylene, C 2-6 alkynylene,

wherein

each m is independently 0, 1, 2, 3 or 4;

Q E and Q W are each independently aryl, heteroaryl, or heterocyclyl,

wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from halo, oxo, —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, —OC 1-6 alkyl, —C 3-8 cycloalkyl, —C 1-6 alkylC 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and R N ;

wherein each alkyl, alkenyl, alkynyl, C 3-8 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, —NR a R b , —C(O)R a , —C(O)OR a , —OC 1-6 alkylCN, —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; and wherein the heteroaryl or heterocyclic group may be oxidized on a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to form a sulfoxide or sulfone;

wherein

R N is independently —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 alkylC(O)NR 1 R 2 , —OC 1-6 alkylC(O)NR 1 R 2 , —OC 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, —OC 1-6 haloalkyl, NR a R b , —C(O)R a , —C(O)OR a , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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;

wherein each alkyl, alkenyl, or alkynyl 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 , —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 NR c (CH 2 ) u 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 R 2 , 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 R 2 , 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 , (CH 2 ) q OR a , 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; and

z is 0, 1, 2, or 3;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl of R E or R W is optionally substituted with 1 to 3 substituents independently selected from 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;

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;

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 ;

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 ;

R 4 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 ;

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;

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 ;

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 e is independently selected from H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —OC 3-8 cycloalkyl, —Oaryl, —Oheteroaryl, —Oheterocyclyl, —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 ;

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

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, stereoisomer, mixture of stereoisomers, or tautomer thereof.

16 . The compound according to claim 1 wherein:

Ar E and Ar W are each independently a cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from halo, —OR a , —NO 2 , —CN, —NR a R b , —N 3 , —SO 2 R a , —C 1-6 alkyl, —C 1-6 haloalkyl, OC 1-6 alkyl, —OC 1-6 haloalkyl, and —C 3-8 cycloalkyl;

wherein each alkyl, and cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from NO 2 , —N 3 , —OR a , halo, and cyano;

or a pharmaceutically acceptable salt, thereof.

17 . The compound according to claim 15 , wherein:

Ar E and Ar W are each independently an aryl, heteroaryl, or heterocyclyl;

wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from halo, —OR a , —CN, —C 1-6 alkyl, —C 1-6 haloalkyl, and —OC 1-6 alkyl;

wherein each alkyl group is optionally substituted with 1 to 4 groups independently selected from —OR a , halo, or cyano;

or a pharmaceutically acceptable salt, thereof.

18 . The compound according to claim 15 , wherein:

Ar W is the same as Ar E and is selected from phenyl, pyridinyl, indanyl, and indolinyl,

wherein each phenyl, pyridinyl, indanyl, and indolinyl is optionally substituted with 1 to 2 groups independently selected from halo, —OR a , CN, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OR a , —C 1-6 haloalkyl, and —C 1-6 cyanoalkyl;

or a pharmaceutically acceptable salt, thereof.

19 . The compound according to any one of claims 15 - 17 , wherein Ar E and Ar W are phenyl each substituted with a methyl group.

20 . The compound according to any one of claims 15 - 18 , wherein:

Ar W is phenyl and Ar E is phenyl wherein each is optionally substituted with halo.

21 . The compound according to claim 1 wherein Ar E and Ar W are each indanyl.

22 . The compound according to any one of claims 15 - 18 , wherein Ar W is indolinyl and Ar E is indolinyl, each optionally substituted with 1 to 2 groups independently selected from methyl, ethyl, methoxy, chloro, and CF 3 .

23 . The compound according to any one of claims 15 - 18 , wherein Ar E is phenyl and Ar W is phenyl each optionally substituted with 1 to 2 groups independently selected from methyl, ethyl, methoxy, chloro, and CF 3 .

24 . The compound according to claims 15 - 18 , wherein Ar E is the same as Ar W wherein each is optionally substituted with 1 to 2 groups independently selected from methyl, chloro, bromo, CN, OCF 3 , CF 3 CH 2 CF 3 , and ethyl.

25 . The compound according to claims 15 - 18 , wherein Ar E is different from Ar W wherein each is optionally substituted with 1 to 2 groups independently selected from methyl, chloro, bromo, CN, OCF 3 , CF 3 CH 2 CF 3 , and ethyl.

26 . The compound according to any one of claims 15 - 18 , wherein L E and L W are each independently a bond, —O—, —(CR 3 R 4 ) m —, —(CR 3 R 4 ) m O(CR 3 R 4 ) m —, —(CR 3 R 4 ) m NR 3 (CR 3 R 4 ) m —, —C(O)—, C 2-6 alkenylene, C 2-6 alkynylene,

and each m is independently 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.

27 . The compound according to any one of claims 15 - 18 , wherein:

L E and L W are each independently a bond, —(CR 3 R 4 ) m —, —(CR 3 R 4 ) m O(CR 3 R 4 ) m —, —C(O)—,

wherein

each m is independently 0, 1, 2 or 3;

R 3 is independently H, —C 1-6 alkyl, —OH, —OCH 3 , or —OCH 2 CH 3 ; and

R 4 is independently H, halo, —C 1-6 alkyl, —OH, —OCH 3 , or —OCH 2 CH 3 ;

or a pharmaceutically acceptable salt thereof.

28 . The compound according to any one of claims 15 - 18 , wherein:

L E and L W are each independently O—, —S—, —SO—, —SO 2 —, —(CR 3 R 4 ) m NR 3 (CR 3 R 4 ) m —, —C(O)—, —(CR 3 R 4 ) m C(O)NR 3 (CR 3 R 4 ) m —, or —(CR 3 R 4 ) m NR 3 C(O)(CR 3 R 4 ) m —,

wherein

each m is independently 0, 1, or 2; and

R 3 and R 4 are each independently H, or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

29 . The compound according to any one of claims 15 - 18 , wherein:

L E and L W are each independently —(CR 3 R 4 ) m —, —O(CR 3 R 4 ) m —, —(CR 3 R 4 ) m O—, or —C(O)—:

wherein

each m is independently 0, 1, 2, or 3; and

R 3 and R 4 are each independently H, or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

30 . The compound according to any one of claims 15 - 18 , wherein:

L E and L W are each independently —CH 2 —, —OCH 2 —, —CH 2 O— or —C(O)—;

or a pharmaceutically acceptable salt thereof.

31 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently aryl, heteroaryl, or heterocyclyl;

wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from halo, oxo, —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 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, —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 2 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 , —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;

wherein the heteroaryl or heterocyclic group may be oxidized on a nitrogen atom to form an N-oxide or oxidized on a sulfur atom to form a sulfoxide or sulfone;

R N is independently —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 alkylOR a , or

wherein

L 1 is independently a bond, O, NR a or S;

L 2 is independently a bond, O, NR a or S;

V is independently selected from a bond, C 1-6 alkyl, and C 2-6 alkenyl; and

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally independently substituted with 1 or 2 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 , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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 and C 3-8 cycloalkyl; halo, —OR a , —N 3 , —NO 2 , —CN, —NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R a , —NR a C(O)R a , —C(O)NR a R b , —C 1-6 alkyl, —OC 1-6 alkyl, and —C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

32 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently aryl, heteroaryl, or heterocyclyl, wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with R N ; and

wherein

L 1 is independently a bond, O, NR a or S;

L 2 is independently a bond, O, NR a or S;

V is independently selected from a bond, C 1-6 alkyl, and C 2-6 alkenyl; and

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally independently substituted with 1 to 2 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 , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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 and C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

33 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or thienyl;

wherein each phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or thienyl is optionally substituted with 1 to 3 groups independently selected from halo, —OR a , —N 3 , —NO 2 , —CN, —NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R a , —NR a C(O)R a , —C(O)NR a R b , —C 1-6 alkyl, —OC 1-6 alkyl, C 3-8 cycloalkyl, and —C 1-6 alkylC 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

34 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or thienyl;

wherein each phenyl, pyridine, indanyl, naphthyl, indolyl, indolinyl, benzthiazolyl, indazolyl, benzimidazolyl, thiazolyl, imidazolyl, or thienyl is optionally substituted with 1 to 2 groups independently selected from halo, —OR a , —N 3 , —NO 2 , —CN, —NR a R b , —C 1-6 alkyl, —OC 1-6 alkyl, C 3-8 cycloalkyl, —C 1-6 alkylC 3-8 cycloalkyl, and R N ; and

wherein

L 1 is independently a bond, O, NR a , S, SO, or SO 2 ;

L 2 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, C 2-6 alkynyl;

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; and

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally independently substituted with 1 to 2 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, CN, NR a R b , —C(O)R a , —C(O)OR a , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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 and C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

35 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently phenyl, pyridine, indazolyl, thiazolyl, or indolinyl;

wherein each phenyl, pyridine, indazolyl, thiazolyl, or indolinyl is optionally substituted with 1 to 3 groups independently selected from halo, —OR a , —CN, —NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R a , —NR a C(O)R a , —C(O)NR a R b , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-8 cycloalkyl, and R N ; and

wherein

L 1 is independently a bond, O, NR a , S, SO, or SO 2 ;

L 2 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, or C 2-6 alkynyl;

wherein each alkyl, alkenyl, or alkynyl group is optionally independently substituted with OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl; and

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally independently substituted with 1 to 2 groups selected from oxo, —NO 2 , —N 3 , —OR a , halo, CN, NR a R b , —C(O)R a , —C(O)OR a , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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 and C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

36 . The compound according to any one of claims 15 - 30 , wherein:

Q E and Q W are each independently aryl, heteroaryl, or heterocyclyl;

wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from OH, halo, CN, —C 1-6 alkyl, —C 1-6 haloalkyl —OC 1-6 alkyl, —OC 1-6 haloalkyl, —SO 2 C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

37 . The compound according to any one of claims 1 - 36 , wherein R E an 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 )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 selected from 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 alkyl C(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 a , —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, —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;

u is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

38 . The compound according to any one of claims 1 - 36 , wherein

R E an R W are independently selected from —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 , and —(CH 2 ) u C(O)NR a SO 2 NR a R b ; and

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , and —C 1-6 alkylC(O)OR a ;

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 ;

R a is independently H or —C 1-6 alkyl;

R b is independently H or —C 1-6 alkyl; and

u is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

39 . The compound according to any one of claims 1 - 36 , wherein R E an R W are independently selected from —(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 selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , or —C 1-6 alkylC(O)OR a ;

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 ;

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.

40 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each independently —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 , or

wherein

V 2 is independently a bond, O, NR a , S, SO or SO 2 ;

L 3 is independently a bond, O, NR a , S, SO, or 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, or 3;

q is independently 0, 1, 2, or 3; and

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, 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;

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , or —C 1-6 alkylC(O)OR a ;

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 ;

or R 1 and R 2 combine to form a heterocyclyl group 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 a is independently H or —C 1-6 alkyl;

R b is independently H or —C 1-6 alkyl;

R e is independently selected from H, OH, —C 1-6 alkyl, and —C 3-8 cycloalkyl;

R d is independently selected from H, —C 1-6 alkyl, and —C 3 -C 8 cycloalkyl;

R e is selected from H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —OC 3-8 cycloalkyl, —Oaryl, —Oheteroaryl, —Oheterocyclyl, —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 ;

R f is independently selected from H, —C 1-6 alkyl, and —C 3-8 cycloalkyl; and

R g is independently selected from H, —C 1-6 alkyl, and —C 3-8 cycloalkyl;

or a pharmaceutically acceptable salt thereof.

41 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each

wherein

V 2 is independently a bond, O, NR a , S, SO, or SO 2 ;

R c is independently selected from H, OH, —C 1-6 alkyl, and —C 3-8 cycloalkyl;

R d is independently selected from H, —C 1-6 alkyl, and —C 3 -C 8 cycloalkyl;

L 3 is independently a bond, O, NR a , S, SO, or SO 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 NR a C(O)R e , or (CH 2 ) q C(O)R e ;

R e is selected from H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —OC 3-8 cycloalkyl, —Oaryl, —Oheteroaryl, —Oheterocyclyl, —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 ;

R f is independently selected from H, —C 1-6 alkyl, and —C 3-8 cycloalkyl;

R g is independently selected from H, —C 1-6 alkyl, and —C 3-8 cycloalkyl;

p is independently 0, 1, 2, or 3;

q is independently 0, 1, 2, or 3; and

z is 0, 1, 2, or 3;

provided that at least one of V 2 , L 3 , ring B and T contains a nitrogen atom;

or a pharmaceutically acceptable salt thereof.

42 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each independently —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , or —OC 1-6 alkylNR 1 R 2 ;

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , or —C 1-6 alkylC(O)OR a ;

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 ;

R a is independently H or —C 1-6 alkyl; and

R b is independently H or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

43 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each —C 1-6 alkylOC 1-6 alkylNR 1 R 2 ;

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , and —C 1-6 alkylC(O)OR a ;

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 ;

R 1 and R 2 combine to form a heterocyclyl group 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 a is independently H or —C 1-6 alkyl; and

R b is independently H or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

44 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each —OC 1-6 alkylNR 1 R 2 ;

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , and —C 1-6 alkylC(O)OR a ;

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 ;

R a is independently H or —C 1-6 alkyl; and

R b is independently H or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

45 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each —NR 1 R 2 ;

R 1 is selected from H, —C 1-6 alkyl, —C 3-6 cycloalkyl, heterocyclyl, —C 2-6 alkyl-OR a , and —C 1-6 alkylC(O)OR a ;

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 ;

R a is independently H or —C 1-6 alkyl; and

R b is independently H or —C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

46 . The compound according to any one of claims 1 - 36 , wherein the groups R E and R W are each independently:

47 . The compound according to any one of claims 1 - 36 , wherein R E and R W are each independently selected from:

48 . The compound according to claim 15 , wherein Ar E and Ar W are each independently aryl, heteroaryl, or heterocyclyl;

wherein each aryl, heteroaryl, or heterocyclyl optionally substituted with 1 to 2 groups independently selected from halo, —OR a , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 haloalkyl, and —C 3-8 cycloalkyl;

L E and L W are each independently a bond, —O—, —(CR 3 R 4 ) m —, —O(CR 3 R 4 ) m , —(CR 3 R 4 ) m O, —(CR 3 R 4 ) m NR 3 —, —NR 3 (CR 3 R 4 ) m —, or —C(O)—;

m is independently 0, 1, 2, 3 or 4; and

Q E and Q W are each independently aryl, heteroaryl, or heterocyclyl;

wherein each aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from halo, —OR a , —N 3 , —NO 2 , —CN, —NR a R b , —SO 2 R a , —SO 2 NR a R b , —NR a SO 2 R a , —NR a C(O)R a , —C(O)NR a R b , —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-8 cycloalkyl, and R N ;

wherein

R N is

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 group 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 independently substituted with 1 to 2 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 , —OC 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR 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;

R E and R W are each independently —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(O)NR 1 R 2 , —(CH 2 ) u SO 2 NR 1 R 2 , —SO 2 NR a C 1-6 alkylNR 1 R 2 , —NR a SO 2 C 1-6 alkylNR 1 R 2 , or

wherein

V 2 is independently a bond, O, NR a , S, SO or SO 2

L 3 is independently a bond, O, NR a , S, SO, or SO 2 ;

ring B is cycloalkyl, aryl, heteroaryl, or heterocyclyl;

T is (CH 2 ) q NR 1 R 2 or (CH 2 ) q C(O)R e ;

p is 0, 1, 2, or 3;

q is 0, 1, 2, or 3;

z is 0, 1, 2, or 3;

and wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group 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;

R 1 is selected from H, —C 1-6 alkylaryl, heterocyclyl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 1-6 alkylC(O)OR a , —C 2-6 alkenylC(O)OR a , and C 1-6 alkylC 3-8 cycloalkyl;

wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 2 groups independently selected from —OR a , oxo, —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 alkyl C(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 , —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 ;

R 2 is selected from —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 , and —C 2-6 alkenylC(O)OR a ;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 3 groups independently selected from —OR a , —CN, halo, —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 optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur or 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 ;

R 3 is independently H, halo, —C 1-6 alkyl, —OH, —OCH 3 , or —OCH 2 CH 3 ;

R 4 is independently H, halo, —C 1-6 alkyl, —OH, —OCH 3 , or —OCH 2 CH 3 ;

R a is independently selected from H, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl;

R b is independently selected from H, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl;

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;

or wherein any two R c , any two R d or any R c and R d optionally combine to form a 3-6 membered cycloalkyl ring;

R e is independently selected from H, —C 1-6 alkyl, —OC 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —OC 3-8 cycloalkyl, —Oaryl, —Oheteroaryl, —Oheterocyclyl, —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 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 ;

or a pharmaceutically acceptable salt thereof.

49 . The compound

or a pharmaceutically acceptable salt thereof.

50 . The compound

or a pharmaceutically acceptable salt thereof.

51 . The compound

or a pharmaceutically acceptable salt thereof.

52 . The compound

or a pharmaceutically acceptable salt thereof.

53 . The compound

or a pharmaceutically acceptable salt thereof.

54 . The compound

or a pharmaceutically acceptable salt thereof.

55 . The compound

or a pharmaceutically acceptable salt thereof.

56 . The compound

or a pharmaceutically acceptable salt thereof.

57 . The compound

or a pharmaceutically acceptable salt thereof.

58 . The compound

or a pharmaceutically acceptable salt thereof.

59 . A method for inhibiting PD-1, PD-L1 and/or the PD-1/PD-L1 interaction comprising administering a compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, to a patient in need thereof.

60 . A method for treating cancer comprising administering a therapeutically effective amount of a compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, to a patient in need thereof.

61 . The method according to claim 60 , wherein the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-cell lung cancer or colon cancer.

62 . The method according to claim 60 , wherein the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma or diffuse large B-cell lymphoma (DLBCL).

63 . The method according to claim 59 or 60 further comprising administering at least one additional anticancer agent or therapy selected from nivolumab, pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiation therapy, and resection therapy, to a patient in need thereof.

64 . The method according to claim 59 or 60 wherein the additional anticancer agent or therapy is nivolumab, pembrolizumab, artezolizumab, and nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

65 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof, and at least one pharmaceutically acceptable excipient.

66 . The pharmaceutical composition according to claim 65 , 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.

67 . The pharmaceutical composition according to claim 65 wherein the additional anticancer agent is nivolumab, pembrolizumab a, atezolizumab, or ipilimumab.

68 . A compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof for use in therapy.

69 . A compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.

70 . A compound according to any one of claims 1 - 58 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and at least one additional anti-cancer agent selected from rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, and ipilimumab for use in the manufacture of a medicament for treating cancer.

71 . A kit for treating or preventing cancer or a disease or condition that is amenable to treatment by inhibiting PD-1, PD-L1 and/or the PD-1/PD-L1 interaction in a patient in need thereof, comprising:

a) a compound according to any of claims 1 - 58 , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof;

b) a monoclonal antibody checkpoint inhibitor or antigen binding fragment thereof; and optionally

c) a label or instructions for use.

72 . A kit for treating or preventing cancer or a disease or condition that is amenable to treatment by inhibiting PD-1, PD-L1 and/or the PD-1/PD-L1 interaction in a patient in need thereof, comprising:

a) a compound according to any of claims 1 - 58 , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof;

b) a monoclonal antibody checkpoint inhibitor or antigen binding fraction thereof; and optionally

c) an additional therapeutic agent; and optionally,

d) a label or instructions for use.

73 . A kit for treating or preventing cancer or a disease or condition in a subject in need thereof, comprising:

a) a compound according to any of claims 1 - 58 , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof;

b) an anti-MMP9 antibody or antigen binding fragment thereof; and optionally

c) an additional therapeutic agent; and optionally;

d) a label or instructions for use.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 7, 2018

From: MACHICAO TELLO, PAULO A; WANG, PEIYUAN

To: GILEAD SCIENCES, INC.

Reel/Frame 045735/0290 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 7, 2018

From: GRAUPE, MICHAEL; SIMONOVICH, SCOTT PRESTON; VENKATARAMANI, CHANDRASEKAR; WATKINS, WILLIAM J

To: GILEAD SCIENCES, INC.

Reel/Frame 045735/0306 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 7, 2018

From: AKTOUDIANAKIS, EVANGELOS; APPLEBY, TODD; CHO, AESOP; DU, ZHIMIN; GUERRERO, JUAN A; JABRI, SALMAN Y; LAD, LATESHKUMAR THAKORLAL; MEDLEY, JONATHAN WILLIAM; METOBO, SAMUEL E; MUKHERJEE, PRASENJIT KUMAR; NADUTHAMBI, DEVAN; NOTTE, GREGORY; PARKHILL, ERIC Q; PHILLIPS, BARTON W; SQUIRES, NEIL H; XU, JIE; YANG, KIN SHING; ZIEBENHAUS, CHRISTOPHER ALLEN

To: GILEAD SCIENCES, INC.

Reel/Frame 045735/0319 →