Immunomodulator compounds

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1a , R 1b , R 1c , and R 1d 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 independently 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 and pyrrolidinyl, each of which is optionally substituted with from 1 to 4 groups independently selected from halogen, CN, hydroxy, oxo, C 1-4 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, —OC(O)(C 1-4 alkyl), —CO 2 (C 1-4 alkyl), and —CO 2 H;

R 2a is H or halogen;

each 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; and 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, oxo, —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 independently selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and CO 2 H, and C 1-8 haloalkyl optionally substituted with 1 to 2 substituents independently selected from OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, and 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, and S, and optionally substituted with oxo; and each R i is independently selected from the group consisting of —OH, 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-SO 3 R j , C 1-8 alkyl-B(OH) 2 , C 1-8 alkyl-PO 3 H 2 , C 1-8 alkyl-C(O)NHOH, C 1-8 alkyl-NR h1 R h2 , —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-C 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 amino acids 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

R h1 and R h2 are each independently selected from the group consisting of H, C 1-6 alkyl, and C 1-4 hydroxyalkyl;

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

each R w 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 , and oxo;

R 4 is selected from the group consisting of O—C 1-8 alkyl, —O—C 1-4 alkyl-C 6 aryl, —O—C 1-4 alkyl-C 4-7 heterocycloalkyl, and —O—C 1-4 alkyl-C 6 heteroaryl, each of which is optionally substituted with 1 or 2 R 4a ;

each R 4a is independently selected from the group consisting of halogen, —CN, —R m , —CONR n R p , and —OR n ;

wherein each R n and R p is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl; and each R m is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 1-8 haloalkyl;

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 , and —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, and 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 is selected from the group consisting of H, C 1-4 alkyl, and C 1-4 haloalkyl;

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

each R 6b is independently selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, and 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, and S, and optionally substituted with oxo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula (Ia)

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula (Ib)

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula (Ia1) or (Ia2):

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 2b and R 2c is independently selected from the group consisting of hydrogen, halogen, CN, C 1-4 alkyl, and C 1-4 haloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —NR g R h .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 4-12 heterocyclyl, wherein the C 4-12 heterocyclyl is optionally substituted with 1 to 6 R 3a .

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein the C 4-12 heterocyclyl is a C 7-11 spiroheterocyclyl and is optionally substituted with 1 to 6 R 3a .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

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

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H and R 2a is halogen.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b and R 2c are both H and R 2a is Cl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6a is H.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.

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

m is 1; and

R 6b is selected from the group consisting of F, C 1-4 alkyl, O—R u , C 1-4 haloalkyl, and 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.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 6b is F.

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

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of