Indanes as PD-L1 inhibitors
Compounds represented by Formula (I) or (II): are provided herein, or a pharmaceutically acceptable salt, or a prodrug or bioisostere thereof; wherein R 1 , R 2a , R 2b , R 2c , R 3 , R 4 , R 5 , R 6a , R 6b , R 2a′ , R 2b′ , R 2c′ , R 3′ , R 4′ , R 5′ , R 6a′ , R 6b′ , Y, Y′, and the subscripts m and n are as defined herein.
1. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.
3. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
4. A compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R 3 and R 3′ are each independently selected from the group consisting of —NR d R e and 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocyclic rings, wherein the 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocyclic rings contain from 1 to 3 N heteroatoms and are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of oxo, —OH, and C 1-8 alkyl;
R d is selected from the group consisting of H and C 1-8 alkyl;
R e is selected from H, —C 1-8 alkyl, —X 2 —CONHSO 2 —C 1-8 alkyl, C 3-10 cycloalkyl, C 4-8 heterocyclyl, and —X 2 —C 4-8 heterocyclyl, wherein the alkyl or alkylene portions of R e are optionally further substituted with from 1 to 2 substituents independently selected from OH, COOH, CONH 2 , and COO—C 1-8 alkyl, and the C 4-8 heterocyclyl and C 3-10 cycloalkyl portions of R e are optionally substituted with 1 substituent independently selected from OH and oxo;
X 2 is a C 1-6 alkylene and is optionally further substituted with OH; and
R 4 and R 4′ are each independently selected from the group consisting of —O-ethyl, —O—CH 2 -pyridyl optionally substituted with 1 —CN, and —O—CH 2 -phenyl optionally substituted with 2 —CN.
5. A compound of Formula (II),
or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
Y′ is O or NH,
each R 2a and R 2a′ is independently selected from the group consisting of H, methyl, Cl, F, and —O-methyl;
R 3 and R 3′ are each independently selected from the group consisting of —NR d R e and 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocyclic rings, wherein the 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocyclic rings contain from 1 to 3 N heteroatoms and are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of —OH and —OC(O)R g ;
R d is selected from the group consisting of H and C 1-8 alkyl;
R e is selected from —C 1-8 alkyl and —C 1-6 alkylene-SO 3 R g , wherein the alkyl or alkylene portions of R e are optionally further substituted with from 1 to 2 substituents independently selected from OH, COOH, and COO—C 1-8 alkyl;
each R g is independently selected from H and C 1-8 alkyl optionally substituted with 1 to 2 NH 2 ;
R 4 and R 4′ are each independently selected from the group consisting of H and −O-ethyl;
m is 0 or 1; and
R 6b′ is F.
6. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently —NR d R e .
10. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently selected from the group consisting of
11. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently a 4- to 9-membered monocyclic or spirocyclic non-aromatic heterocyclic ring containing from 1 to 3 N heteroatoms and optionally substituted with from 1 to 2 substituents independently selected from the group consisting of oxo, —OH, and C 1-8 alkyl.
12. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently a piperidine, azetidine, pyrrolidine, 2λ 2 -azaspiro[3.3]heptane, or 1λ 2 ,3λ 2 ,7λ 2 -triazaspiro[4.4]nonane ring which is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of oxo, —OH, and C 1-8 alkyl.
13. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently an azetidine, 2λ 2 -azaspiro[3.3]heptane, or 1λ 2 ,3λ 2 ,7λ 2 -triazaspiro[4.4]nonane ring which is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of oxo, —OH, and C 1-8 alkyl.
14. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently selected from the group consisting of
15. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.
16. A pharmaceutical composition comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Y′ is O.
18. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently —NR d R e .
19. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently selected from the group consisting of
20. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently a 4- to 6-membered monocyclic or spirocyclic non-aromatic heterocyclic ring containing 1 N heteroatom and optionally substituted with from 1 to 2 substituents independently selected from the group consisting of —OH and —OC(O)R g .
21. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently a piperidine ring which is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of —OH and —OC(O)R g .
22. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 3 and R 3′ is independently selected from the group consisting of
23. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer.
24. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.