Compounds for treatment of PD-L1 diseases

1. A compound of Formula (I):

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

R 1a , R 1b , R 1c and R 1d are each independently selected from the group consisting of H, F, Cl, 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 1-2 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 14 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, and CO 2 H;

or R 2a and R 2b are combined to form a 4- to 8-membered ring or spirocyclic ring, optionally having one or two additional ring vertices selected from O, N or S;

or R 1a and R 2a or X 1 are combined to form a 5- to 7-membered ring;

or R 1b and R 2b or X 1 are combined to form a 5- to 7-membered ring;

wherein the rings formed by combining R 2a and R 2b , R 1a and R 2a or X 1 , or R 1b and R 2b or X 1 , are substituted with 0 to 4 substituents independently selected from the group consisting of oxo, C 1-8 alkyl, C 1-8 haloalkyl, —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 is 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;

the subscript n is 0, 1 or 2;

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

each of R 4 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 1 , —X 4 —C(O) 2 R a , —X 4 —OR a , —X 4 —NR a R b , —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 , —O—X 4 —Y 1 and —X 4 —Y 1 wherein each X 4 is a bond or 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, and each Y 1 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, 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, and CO 2 H;

R 5 is a member selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —Y 2 , —X 5 —C(O) 2 R a , —X 5 —OR a , —X 5 —NR a R b , —X 5 —CONR a R b , —X 5 —SO 2 R a , —X 5 —SO 2 NR a R b , —X 5 —SO 3 R a , —X 5 —Y 2 , —O—X 5 —Y 2 and -A-Z, wherein each X 5 is a bond or 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, and each Y 2 is selected from the group consisting of C 3-6 cycloalkyl, C 4-8 heterocyclyl, C 7-9 spiroheterocyclyl, 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, halogen, 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, and CO 2 H;

wherein

A is a member selected from the group consisting of a bond, —O— and N(R a );

Z is selected from the group consisting of:

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

ii) phenyl, optionally substituted with one to three Re; and

iii) a 5- or 6-membered non-aromatic heterocyclic ring, optionally substituted with one to three R c ;

and when A is —O— or N(R a )—, then Z is other than phenyl;

and two of R 4 , R 5 , R 6 , R 7 and R 8 on adjacent carbon atoms are optionally combined to form a 5- or 6-membered non-aromatic heterocyclic ring having one or two ring vertices selected from the group consisting of O, —N(R b )— and ═N—; wherein said non-aromatic heterocyclic ring is optionally substituted with oxo and optionally with from one to four R e ;

and at least one of R 4 , R 5 , R 6 , R 7 and R 8 is other than H;

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-COO—C 1-8 alkyl, 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, C 1-6 alkylene-SO 3 H and C 1-6 alkylene-Y 3 , wherein Y 3 is C 3-6 cycloalkyl or C 4-8 heterocyclyl, and each R b is optionally further substituted with one or two members independently selected from oxo, 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 4 , —X 6 —C(O) 2 R a , —X 6 —OR a , —X 6 —NR a R b , —X 6 —CONR a R b , —X 6 —SO 2 R a , —X 6 —SO 2 NR a R b , —X 6 —SO 3 R a , and —N(R a )—X 6 —C(O) 2 R a , wherein each X 6 is a bond or C 1-6 alkylene, and each Y 4 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 wherein R 5 is -A-Z.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 5 is —O—X 5 —Y 2 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 5 is -A-Z, A is a bond, and Z is phenyl, optionally substituted with one to three R c .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein X t is —CH 2 —.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1c , R 7 and R 8 are H, and R 3 is selected from the group consisting of F, Cl, CH 3 , CF 3 and OCH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein a ring is formed between one pair of R 4 and R 5 , R 5 and R 6 , R 1b and R 2b , or R 1a and R 2a .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 5 is -A-Z, and Z is selected from the group consisting of piperidinyl, imidazolyl and pyridinyl.

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

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 4 is selected from the group consisting of F, Cl, CH 3 , CF 3 and OCH 3 .

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

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

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2a and R 2b are combined to form a 4- to 8-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.

14. 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 1 —Y.

15. The compound of claim 14 , 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, and CO 2 H.

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

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

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

19. The compound of claim 17 , or a pharmaceutically acceptable salt thereof wherein Y 2 is selected from the group consisting of:

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

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