Triaryl compounds for treatment of PD-L1 diseases

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, prodrug or bioisostere thereof, wherein:

R 1a , R 1b , R 1c and R 1d are each independently selected from the group consisting of H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and CN;

X 1 is C 1-3 alkylene, optionally substituted with one or two C 1-2 alkyl or CO 2 H;

R 2a and R 2b are each independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, —Y, —X 2 —C(O) 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —CONR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , —X 2 —SO 3 R a and —X 2 —Y wherein each X 2 is C 1-6 alkylene and any C 1-8 alkyl or C 1-6 alkylene, is optionally further substituted with one or two members independently 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, and each Y is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl and 5- to 6-membered heteroaryl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, SO 3 H and CO 2 H;

or R 1a and R 2b are combined to form a 4- to 10-membered ring or spirocyclic ring, optionally having one or two additional ring vertices selected from O, N or S;

wherein the ring formed by combining R 2a and R 2b , is substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 3 —C(O) 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —CONR a R b , —X 3 —SO 2 R a , —X 3 —SO 2 NR a R b , and X 3 —SO 3 R a ; wherein X 3 is a bond or C 1-6 alkylene;

R 3 and R 4 are each independently selected from the group consisting of F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 and CF 3 ;

the subscript n is 0, 1, 2 or 3;

each R 3a is independently selected from the group consisting of H, F, Cl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 2-3 alkenyl and CN;

R 6 , R 7 and R 8 are each independently selected from the group consisting of H, F, Cl, CN, CH 3 , OCH 3 , CH 2 CH 3 and CF 3 ;

A is a member selected from the group consisting of —N(R a )—, —C(═O)N(R a )—, —S(O)N(R a )—, and —S(O) 2 N(R a )—;

Z is selected from the group consisting of:

i) a monocyclic, bicyclic, or spirocyclic non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with up to four R a and/or R b ;

ii) a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and

iii) a fused bicyclic heteroaryl ring, optionally substituted with one to three R c ;

wherein when A is —N(R a )—, then Z is a fused bicyclic heteroaryl ring optionally substituted with one to three R c ;

each R a is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, C 1-6 alkylene-SO 3 H;

each R b is independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene-CO 2 H, and C 1-6 alkylene-SO 3 H, each of which is optionally further substituted with one or two members 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 R a and R b , when attached to the same nitrogen atom, are optionally combined to form a 4- to 8-membered ring or spirocyclic ring, optionally substituted with halogen, OH, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl or CO 2 H;

each R c is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1 - 6 haloalkyl, —Y 1 , —X 4 —C(O) 2 R a , —O—X 4 —C(O) 2 R a , —X 4 —OR a , —X 4 —NR a R b , —X 4 —CONR a R b , —O—X 4 —CONR a R b , —X 4 —SO 2 R a , —X 4 —SO 2 NR a R b , —X 4 —SO 3 R a , and —N(R a )—X 4 —C(O) 2 R a , wherein each X 4 is a bond or C 1-6 alkylene, and each Y 1 is selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl; and optionally two R c on adjacent ring vertices are combined to form a fused 5- or 6-membered heterocyclic ring.

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

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

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof having formula (Id):

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the group R 1a is OCH 3 and R 1b is F.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—, and Z is selected from the group consisting of:

i) a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with up to four R a and/or R b ; and

ii) a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a non-aromatic heterocyclic ring having a formula selected from the group consisting of:

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and said heterocyclic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionally substituted with up to four R a and/or R b .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is —N(R a )—, and Z is a fused bicyclic heteroaryl ring, optionally substituted with one to three R c .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein Z is a fused bicyclic heteroaryl ring having a formula selected from the group consisting of:

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

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, optionally having one or two additional ring vertices selected from O, N or S; wherein said ring or spirocyclic ring is substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —X 2 —C(O) 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —CONR a R b , —X 2 —SO 2 R a , —X 2 —SO 2 NR a R b , and —X 2 —SO 3 R a ; wherein X 2 is a bond or C 1-6 alkylene.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein —N(R 2a )(R 2b ) is selected from the group consisting of:

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a is H or C 1-8 alkyl; and R 2b is —Y or —X 2 —Y.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.

20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof wherein Y is selected from the group consisting of C 3-6 cycloalkyl and C 4-8 heterocyclyl, each of which is optionally further substituted with one to four substituents independently selected from the group consisting of oxo, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, SO 2 NH 2 , CONH 2 , C(O)NHOH, PO 3 H 2 , COO—C 1-8 alkyl, SO 3 H and CO 2 H.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )— and Z is a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with R a and/or R b .

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )— and Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c .

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—; Z is a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with R a and/or R b ; and each of R 1e , R 6 , R 7 and R 8 is H.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—; Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and each of R 1c c, R 6 , R 7 and R 8 is H.

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—; Z is a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with R a and/or R b ; and said non-aromatic heterocyclic ring is selected from the group consisting of piperidinyl, morpholinyl, tetrahydropyranyl, and tetrahydrofuranyl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein A is —C(═O)N(R a )—; Z is a monocyclic 5- or 6-membered heteroaryl ring, optionally substituted with one to three R c ; and said heterocyclic ring is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, and pyrazolyl.

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

28. 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.

29. 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.

30. 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.

31. A method of treating a subject suffering from a disease or disorder mediated by the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

32. The method of claim 28 , further comprising administering to the subject a therapeutically effective amount of one or more additional therapeutic agents.