Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases

Inventors: Pingchen Fan (Fremont, CA); Christopher W. Lange (Hayward, CA); Rebecca M. Lui (Mountain View, CA); Darren J. McMurtrie (Sunnyvale, CA); Ryan J. Scamp (Fremont, CA); Ju Yang (Palo Alto, CA); Yibin Zeng (Foster City, CA); Penglie Zhang (Foster City, CA)

Assignee: CHEMOCENTRYX, INC.

C07D401/14 C07D401/12 C07D403/14 C07D405/14 C07D487/10

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Quick Facts

Patent No.: US 11,713,307
App. No.: 17/071,077
Granted: Aug 1, 2023
Kind: B2

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Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 2a , R 2b , R 3 , R 3a , R 4 , R 6 , R 7 , R 8 , A, Z, X 1 and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Claims (52)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:

A is a 5- to 10-membered heteroaryl group which is unsubstituted or substituted with from one to five members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and CN;

X 1 is C 1-3 alkylene, which is unsubstituted or substituted with one or two members independently selected from the group consisting of C 1-2 alkyl and 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 —CO 2 R a , —X 2 —OR a , —X 2 —NR a R b , —X 2 —C(O)NR 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, any C 1-8 alkyl or C 1-6 alkylene is unsubstituted or substituted with one or two members independently selected from the group consisting of OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 —C 1-8 alkyl and 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 unsubstituted or 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 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H and CO 2 H;

or R 2a and R 2b are combined to form a 4- to 9-membered ring or spirocyclic ring, having from zero to two additional heteroatom ring vertices selected from O, N or S;

wherein the ring formed by combining R 2a and R 2b , is unsubstituted or substituted with 1 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 —CO 2 R a , —X 3 —OR a , —X 3 —NR a R b , —X 3 —C(O)NR 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 3′ 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 ;

Z is a 6-membered monocyclic 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 ;

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, and 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 unsubstituted or substituted with one or two members independently selected from OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 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, which is unsubstituted or substituted with halogen, OH, SO 2 NH 2 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl or CO 2 H.

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, wherein A is a 5- or 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and CN.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group which is unsubstituted or substituted with from one to three members independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and CN.

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH 3 and F.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl selected from the group consisting of pyridine, pyrimidine, pyrazine and 1,2,4-triazine, each of which is unsubstituted or substituted with one or two members independently selected from the group consisting of OCH 3 and F.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 6-membered monocyclic 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 6-membered monocyclic non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, and tetrahydropyranyl each of which is optionally substituted with up to four R a and/or R b .

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

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

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

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

14. The compound of claim 1 , 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 unsubstituted or 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 , C(O)NH 2 , C(O)NHOH, PO 3 H 2 , CO 2 C 1-8 alkyl, SO 3 H and CO 2 H.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 6-membered monocyclic non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with one R a and/or one R b .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 6-membered monocyclic non-aromatic heterocyclic ring, optionally substituted with one or two oxo groups and optionally substituted with one R a and/or one R b ; and each of R 6 , R 7 and R 8 is H.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a 6-membered monocyclic non-aromatic heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, and tetrahydropyranyl, optionally substituted with one or two oxo groups and optionally substituted with one R a and/or one R b .

18. The compound of claim 1 , wherein said compound is selected from the group consisting of