Macrocyclic immunomodulators

1. A compound of Formula (I) or Formula (II):

or a pharmaceutically acceptable salt thereof; wherein:

R is selected from the group consisting of H, halogen, CN, C 1-3 haloalkyl, C 1-3 alkyl and C 1-3 alkoxy;

R 1 is selected from the group consisting of halogen, C 5-8 cycloalkyl, C 6-10 aryl and thienyl, wherein the C 6-10 aryl and thienyl are optionally substituted with 1 to 5 R 1a substituents;

each R 1a independently selected from the group consisting of halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a ,—O—X 1 —CO 2 R a , —O—X 1 —CONR a R b , —X 1 —OR 3 , —X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , and —S(O) 2 NR a R b , wherein each X 1 is a C 1-4 alkylene; each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, wherein the five or six-membered ring is optionally substituted with oxo; each R c is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl and C 1-8 haloalkyl; and optionally when two R 1a substituents are on adjacent atoms, they are combined to form a fused five, six or seven-membered carbocyclic or heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from halogen, oxo, C 1-8 haloalkyl and C 1-8 alkyl; or

R 1 is

wherein

each of R 1b , R 1c , R 1d and R 1e is independently selected from the group consisting of H, halogen, CF 3 , CN, C 1-4 alkyl and —O—C 1-4 alkyl, wherein the C 1-4 alkyl and —O—C 1-4 alkyl are optionally further substituted with halogen, hydroxyl, methoxy or ethoxy;

L is a linking group selected from the group consisting of:

wherein each of the subscripts q is independently 1, 2, 3 or 4, and L is optionally further substituted with one or two members selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl and —CO 2 H;

Z is selected from the group consisting of azetidinyl, pyrollidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, guanidinyl, quinuclidine, and 8-azabicyclo[3.2.1]octane, each of which is optionally substituted with from 1 to 3 groups independently selected from halogen, hydroxy, C 1-3 alkyl, —NH 2 , —NHC 1-3 alkyl, —N(C 1-3 alkyl) 2 , —O—C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 haloalkyl and —CO 2 H;

or

Z is selected from the group consisting of —CO 2 R z1 and —NR z1 R z2 ; wherein R z1 is selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 hydroxyalkyl; and R z2 is selected from —C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl-COOH, C 1-8 alkyl-OH, C 1-8 alkyl-CONH 2 , C 1-8 alkyl-SO 2 NH 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, —C(O)—C 1-8 alkyl-OH, —C(O)—C 1-8 alkyl-COOH, C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOH, —C 3-10 cycloalkyl-OH, C 4-8 heterocyclyl, —C 4-8 heterocyclyl-COOH, —C 4-8 heterocyclyl-OH, —C 1-8 alkyl-C 4-8 heterocyclyl, —C 1-8 alkyl-C 3-10 cycloalkyl, C 5-10 heteroaryl and —C 1-8 alkyl-C 5-10 heteroaryl;

each R 2a , R 2b and R 2c is independently selected from the group consisting of H, halogen, —CN, —R d , —CO 2 R e , —CONR e R f , —OC(O)NR e R f , —NR f C(O)R e , —NR f C(O) 2 R d , —NR e —C(O)NR e R f , —NR e R f , —OR e , —X 2 —OR e , —X 2 —NR e R f , —X 2 —CO 2 R e , —SF 5 , and —S(O) 2 NR e R f , wherein each X 2 is a C 1-4 alkylene; each R e and R f is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with oxo; each R d is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;

R 3 is selected from the group consisting of —NR g R h and C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R 3a ;

each R 3a is independently selected from the group consisting of halogen, —CN, R i , —CO 2 R j , —CONR j R k , —CONHC 1-6 alkyl-OH, —C(O)R j , —OC(O)NR j R k , —NR j C(O)R k , —NR j C(O) 2 R k , —CONHOH, —PO 3 H 2 , —NR j —X 3 —C(O) 2 R k , —NR j C(O)NR j R k , —NR j R k , —OR j , —S(O) 2 NR j R k , —O—X 3 —OR j , —O—X 3 —NR j R k , —O—X 3 —CO 2 R j , —O—X 3 —CONR j R k , —X 3 —OR j , —X 3 —NR j R k , —X 3 —CO 2 R j , —X 3 —CONR j R k , —X 3 —CONHSO 2 R j and SF 5 ; wherein X 3 is C 1-6 alkylene and is optionally further substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, wherein each R j and R k is independently selected from hydrogen, C 1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2, CONH 2 , C(O)NHOH, PO 3 H 2 , B(OH) 2 , COO—C 1-8 alkyl or CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H, or when attached to the same nitrogen atom R j and R k can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R i is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl each of which may be optionally substituted with OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H;

R g is selected from the group consisting of H, C 1-8 haloalkyl and C 1-8 alkyl;

R h is selected from C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkyl-CO 2 R j , C 1-8 alkyl-CONR j R k , C 1-8 alkyl-CONHSO 2 R j , C 1-8 alkyl-SO 2 NR j R k , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, C 1-8 alkyl-NR j R k , —C(O)R j , C 3-10 cycloalkyl, —C 3-10 cycloalkyl-COOR j , —C 3-10 cycloalkyl-OR j , C 4-8 heterocyclyl, —C 4-8 heterocyclyl-COOR j , —C 4-8 heterocyclyl-OR j , —C 1-8 alkyl-C 4-8 heterocyclyl, —C(═O)OC 1-8 alkyl-C 4-8 heterocyclyl, —C 1-8 alkyl-C 3-10 cycloalkyl, C 5-10 heteroaryl, —C 1-8 alkyl- 5-10 heteroaryl, —C 1-8 alkyl-C 6-10 aryl, —C 1-8 alkyl-(C═O)—C 6-10 aryl, —CO 2 —C 1-8 alkyl-O 2 C—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkenyl , —C 1-8 alkyl-NH(C═O)—C 1-8 alkyl, —C 1-8 alkyl-NH(C═O)—C 2-8 alkynyl, —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-COOR j , and —C 1-8 alkyl-(C═O)—NH—C 1-8 alkyl-OR j optionally substituted with CO 2 H; or

R h combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein

the non-natural aminoacids have an alpha carbon substituent selected from the group consisting of C 2-4 hydroxyalkyl, C 1-3 alkyl-guanidinyl, and C 1-4 alkyl-heteroaryl,

the alpha carbon of each natural or non-natural amino acid is optionally further substituted with a methyl group, and

the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O—C 1-6 alkyl, and PO 3 H 2 , wherein

the C 1-8 alkyl portions of R h are optionally further substituted with from 1 to 3 substituents independently selected from OH, COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, COO—C 1-4 alkyl, PO 3 H 2 and C 5-6 heteroaryl optionally substituted with 1 to 2 C 1-3 alkyl substituents,

the C 5-10 heteroaryl and the C 6-10 aryl portions of R h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) 2 , COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-C(O)NHOH, C 1-4 alkyl-PO 3 H 2 , C 1-4 alkyl-COOH, and phenyl;

the C 4-8 heterocyclyl and C 3-10 cycloalkyl portions of R h are optionally substituted with 1 to 4 R h1 substituents;

each R h1 substituent is independently selected from C 1-4 alkyl, C 1-4 alkyl-OH, C 1-4 alkyl-COOH, C 1-4 alkyl-SO 2 NH 2 , C 1-4 alkyl CONH 2 , C 1-4 alkyl-C(O)NHOH, C 1-4 alkyl-PO 3 H, OH, COO—C 1-8 alkyl, COOH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , B(OH) 2 and oxo;

R 4 is selected from the group consisting of O—C 1-8 alkyl, O—C 1-8 haloalkyl, C 6-10 aryl, C 5-10 heteroaryl, —O—C 1-4 alkyl-C 4-7 heterocycloalkyl, —O—C 1-4 alkyl-C 6-10 aryl and —O—C 1-4 alkyl-C 5-10 heteroaryl, each of which is optionally substituted with 1 to 5 R 4a ;

each R 4a is independently selected from the group consisting of halogen, —CN, —R m ,—CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , —S(O) 2 R n R p , —S(O) 2 NR n R p , C 3-7 cycloalkyl and C 4-7 heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl rings are optionally substituted with 1 to 5 R t , wherein each R t is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, —CO 2 R n , —CONR n R p , —C(O)R n , —OC(O)NR n R p , —NR n C(O)R p , —NR n C(O) 2 R m , —NR n —C(O)NR n R p , —NR n R p , —OR n , —O—X 4 —OR n , —O—X 4 —NR n R p , —O—X 4 —CO 2 R n , —O—X 4 —CONR n R p , —X 4 —OR n , —X 4 —NR n R p , —X 4 —CO 2 R n , —X 4 —CONR n R p , —SF 5 , and —S(O) 2 NR n R p ;

wherein each X 4 is a C 1-6 alkylene; each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl; and optionally when two R 4a substituents are on adjacent atoms, they are combined to form a fused five or six-membered carbocyclic or heterocyclic ring optionally substituted with oxo;

and wherein R 3 and R 4 are joined to form a 12- to 20-membered macrocycle;

n is 0, 1, 2 or 3;

each R 5 is independently selected from the group consisting of halogen, —CN, —R q , —CO 2 R r , —CONR r R s , —C(O)R r , —OC(O)NR r R s , —NR r C(O)R s , —NR r C(O) 2 R q , —NR r —C(O)NR r R s , —NR r R s , —OR r , —O—X 5 —OR r , —O—X 5 —NR r R s , —O—X 5 —CO 2 R r , —O—X 5 —CONR r R s , —X 5 —OR r , —X 5 —NR r R s , —X 5 —CO 2 R r , —X 5 —CONR r R s , —SF 5 , —S(O) 2 NR r R s , wherein each X 5 is a C 1-4 alkylene; each R r and R s is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R q is independently selected from the group consisting of C 1-8 alkyl, and C 1-8 haloalkyl;

R 6a and R 6c are each independently selected from the group consisting of H, C 1-4 alkyl and C 1-4 haloalkyl;

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

each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, NR u R v , wherein each R u and R v is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo.

2. A compound of claim 1 , having Formula (I).

3. A compound of claim 1 , having Formula (II).

4. A compound of claim 1 , having Formula (Ia) or Formula (IIa)

or a pharmaceutically acceptable salt thereof; wherein:

W is N or C(R9);

X, Y and V are each independently selected from the group consisting of a bond, O, NH, N(CH 3 ), C(O), methylene and ethylene, wherein the methylene and ethylene are optionally substituted with one or two R 7a ;

R 1 is selected from the group consisting of C 6-10 aryl and thienyl, each of which is optionally substituted with 1 to 5 R 1a substituents;

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, CH 2 OH, —CO 2 —(C 1-6 alkyl) and PO 3 H 2, wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2, CN, and CO 2 H;

each R 8a and R 8b is independently selected from the group consisting of H and C 1-6 alkyl, optionally substituted with halogen, OH, NH 2 , CN, and CO 2 H; and

R 9 a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 —C 1-6 alkyl, —C 1-6 alkyl-C(O)NH 2 , —C 1-6 alkyl-C(O)NHC 1-6 alkyl and —C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 .

5. A compound of claim 4 , having Formula (Ia).

6. A compound of claim 4 , having Formula (IIa).

7. A compound of claim 1 , having Formula (Ib) or Formula (IIb)

or a pharmaceutically acceptable salt thereof; wherein:

W is N or C(R 9 );

X, Y and V are each independently selected from the group consisting of a bond, O, NH, N(CH 3 ), C(O), methylene and ethylene, wherein the methylene and ethylene are optionally substituted with one or two R 7a ;

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, CH 2 OH, —CO 2 —(C 1-6 alkyl) and PO 3 H 2 , wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2 , CN, and CO 2 H;

each R 8a and R 8b is independently selected from the group consisting of H and C 1-6 alkyl, optionally substituted with halogen, OH, NH 2 , CN, and CO 2 H; and

R 9 a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 —C 1-6 alkyl, —C 1-6 alkyl-C(O)NH 2 , —C 1-6 alkyl-C(O)NHC 1-6 alkyl and —C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 .

8. A compound of claim 7 , having Formula (Ib).

9. A compound of claim 7 , having Formula (IIb).

10. A compound of claim 1 , having Formula (Ic) or Formula (IIc)

or a pharmaceutically acceptable salt thereof; wherein:

X 9 is C 1-8 alkylene;

X, Y and V are each independently selected from the group consisting of a bond, O, NH, N(CH 3 ), C(O), methylene and ethylene, wherein the methylene and ethylene are optionally substituted with one or two R 7a ;

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, CH 2 OH, —CO 2 —(C 1-6 alkyl) and PO 3 H 2 , wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2 , CN, and CO 2 H; and

each R 8a and R 8b is independently selected from the group consisting of H and C 1-6 alkyl, optionally substituted with halogen, OH, NH 2 , CN, and CO 2 H.

11. A compound of claim 10 , having Formula (Ic).

12. A compound of claim 10 , having Formula (IIc).

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein the macrocycle formed by joining R 3 and R 4 is a 15- or 16-membered macrocycle.

14. A compound of claim 1 , having Formula (Ia1) or Formula (IIa1)

or a pharmaceutically acceptable salt thereof; wherein:

W is N or C(R 9 );

R 1 is selected from the group consisting of C 6-10 aryl and thienyl, each of which is optionally substituted with 1 to 5 R 1a substituents;

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, —CO 2 —(C 1-6 alkyl) and PO 3 H 2 , wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2 , CN, and CO 2 H; and

R 9 a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 —C 1-6 alkyl, —C 1-6 alkyl-C(O)NH 2 , —C 1-6 alkyl-C(O)NHC 1-6 alkyl and —C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 .

15. A compound of claim 14 , having Formula (Ia1).

16. A compound of claim 14 , having Formula (IIa1).

17. A compound of claim 14 , wherein R 9 is CN.

18. A compound of claim 14 , wherein each R 7a and R 7b is independently selected from the group consisting of H, CO 2 H, and CH 2 OH.

19. A compound of claim 1 , having Formula (Ib1) or Formula (IIb1):

or a pharmaceutically acceptable salt thereof; wherein:

W is N or C(R 9 );

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, —CO 2 —(C 1-6 alkyl) and PO 3 H 2 , wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2 , CN, and CO 2 H;

R 9 a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 —C 1-6 alkyl, —C 1-6 alkyl-C(O)NH 2 , —C 1-6 alkyl-C(O)NHC 1-6 alkyl and —C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 .

20. A compound of claim 19 , having Formula (Ib1).

21. A compound of claim 19 , having Formula (IIb1).

22. A compound of claim 19 , wherein R 9 is CN.

23. A compound of claim 19 , wherein each R 7a and R 7b is independently selected from the group consisting of H, CO 2 H, and CH 2 OH,.

24. A compound of claim 1 , having Formula (Ic1) or Formula (IIc1):

or a pharmaceutically acceptable salt thereof; wherein:

W is N or C(R 9 );

each R 7a and R 7b is independently selected from the group consisting of H, C 1-6 alkyl, CO 2 H, CH 2 OH, —CO 2 —(C 1-6 alkyl) and PO 3 H 2 , wherein C 1-6 alkyl is optionally substituted with one or two members selected from halogen, OH, NH 2 , CN, and CO 2 H;

R 9 a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 (C 1-6 alkyl), —C 1-6 alkyl-CO 2 H, —C 1-6 alkyl-CO 2 —C 1-6 alkyl, —C 1-6 alkyl-C(O)NH 2 , —C 1-6 alkyl-C(O)NHC 1-6 alkyl and —C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 .

25. A compound of claim 24 , having Formula (Ic1).

26. A compound of claim 24 , having Formula (IIc1).

27. A compound of claim 24 , wherein R 9 is CN.

28. A compound of claim 24 , wherein each R 7a and R 7b is independently selected from the group consisting of H, CO 2 H, and CH 2 OH.

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl, optionally substituted with 1 to 3 R 1a substituents.

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl, optionally substituted with 1 to 3 R 1a substituents wherein each R 1a is independently selected from halogen, C 1-8 alkyl, O—C 1-8 alkyl, O—C 1-8 haloalkyl, —NR a R b , and CN, and optionally when two R 1a substituents are on adjacent atoms, they are combined to form a fused six-membered heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from oxo, C 1-8 haloalkyl and C 1-8 alkyl.

31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is selected from the group consisting of:

32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z-L- is a member selected from the group consisting of:

33. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z-L- is a member selected from the group consisting of:

34. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z-L- is a member selected from the group consisting of:

35. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is phenyl, optionally substituted with F.

36. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2a , R 2b and R 2c is independently selected from the group consisting of H, halogen, —CN, —R d , —NR e R f , —OR e , —X 2 —OR e , —X 2 —NR e R f , wherein X 2 is C 1-4 alkylene; each R e and R f is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R d is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl.

37. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

38. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition of claim 38 , further comprising one or more additional therapeutic agents.

40. The pharmaceutical composition of claim 39 , wherein the one or more additional therapeutic agent is selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulatory agent, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and an anti-proliferation agent.

41. A method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

42. A method of enhancing, stimulating, modulating and/or increasing the immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

43. A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

44. The method of claim 41 , wherein the subject suffers from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer.

45. The method of claim 41 , further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.

46. The method of claim 45 , wherein the one or more additional therapeutic agents is selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulatory agent, a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an immunotherapeutic agent, an anti-hormonal agent, an anti-fibrotic agent, radiotherapy, a radiotherapeutic agent, an anti-neoplastic agent, and an anti-proliferation agent.