Inhibitors of CD73-mediated immunosuppression
Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.
1. A compound having the formula:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
R 1a and R 1b are independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted —C(R 2a R 2b )-aryl, —C(R 2a R 2b )—O—C(O)—OR 3 , —C(R 2a R 2b )—O—C(O)R 3 , and —C(R 2a R 2b )C(O)OR 3 ; or, R 1a and R 1b groups are combined to form a 5- to 6-membered heterocyclic ring;
each R 2a and R 2b is independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl;
each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 4 alkoxy(C 1 -C 4 )alkyl and optionally substituted aryl;
R 5a and R 5b are independently selected from the group consisting of H, optionally substituted C 1 -C 6 alkyl, —C(O)OR 3 , C 3 -C 6 cycloalkyl(C 1 -C 6 )alkyl aryl(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl and aryl;
each X is selected from the group consisting of O, NH, and S;
A is:
which is optionally substituted with from 1 to 5 R 6 substituents;
Z is selected from the group consisting of NH, NR 6 , and O;
each R 6 is independently selected from the group consisting of CH 3 , OR g , CN, F, and optionally substituted C 1 -C 6 alkyl; or two R 6 groups on adjacent ring vertices are optionally joined together to form a 5- to 6-membered ring having at least one heteroatom as a ring vertex; and
Het is selected from the group consisting of:
wherein the wavy line indicates the point of attachment to the remainder of the compound,
wherein each G, when present, is independently selected from the group consisting of N and CR e , and wherein:
R a is selected from the group consisting of NHR 7a , NHC(O)R 7a , NR 7a R 7b , R 7a , SR 7a and OR 7a ;
R b is selected from the group consisting of H, halogen, NH 2 , NHR 7a , NR 7a R 7b , R 7a , OH, and OR 7a ;
R c and R d are independently selected from the group consisting of H, halogen, haloalkyl, NH 2 , NHR 7a , NR 7a R 7b , R 7a , OH, OR 7a , SR 7a ,
SO 2 R 7a , —X 1 —NH 2 , —X 1 —NHR 7a , —X 1 —NR 7a R 7b , —X 1 —OH, —X 1 —OR 7a , —X 1 —SR 7a
and —X 1 —SO 2 R 7a ;
each R e is independently selected from the group consisting of H, halogen, and optionally substituted C 1 -C 6 alkyl;
each R g is independently selected from the group consisting of H and —C(O)—C 1 -C 6 alkyl;
each X 1 is C 1 -C 4 alkylene; and
each R 7a and R 7b is independently selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, 4-7 membered cycloheteroalkyl, 4-7 membered cycloheteroalkylC 1 -C 4 alkyl, aryl, arylC 1 -C 4 alkyl, arylC 2 -C 4 alkenyl, arylC 2 -C 4 alkynyl, heteroaryl, heteroarylC 1 -C 4 alkyl, heteroarylC 1 -C 4 alkenyl, and heteroarylC 2 -C 4 alkynyl; or R 7a and R 7b when attached to the same nitrogen atom are optionally joined together to form a 4- to 7-membered heterocyclic ring, optionally fused to an aryl ring.
2. The compound of claim 1 , wherein A is selected from the group consisting of:
3. The compound of claim 1 , wherein Het is:
4. The compound of claim 3 , wherein R c is other than hydrogen.
5. The compound of claim 4 , having a formula selected from the group consisting of:
6. The compound of claim 5 , wherein each X is oxygen.
7. The compound of claim 6 , wherein R e is hydrogen.
8. The compound of claim 7 , wherein each R g is hydrogen.
9. The compound of claim 5 , having the formula:
10. The compound of claim 9 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.
11. The compound of claim 9 , having the formula:
12. The compound of claim 5 , having the formula:
13. The compound of claim 12 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.
14. The compound of claim 12 , having the formula:
15. The compound of claim 5 , having the formula:
16. The compound of claim 15 , wherein R 1a and R 1b are H; each X is O; R g is H; and R g is Cl.
17. The compound of claim 15 , having the formula:
18. The compound of claim 5 , having the formula:
19. The compound of claim 18 , wherein R 1a and R 1b are H; each X is O; R g is H; and R c is Cl.
20. The compound of claim 18 , having the formula:
21. The compound of claim 1 , wherein R 5a is selected from the group consisting of H, optionally substituted C 1-4 alkyl, —C(O)OR 3 , C 3 -C 6 cycloalkyl(C 1 -C 4 )alkyl and aryl(C 1 -C 4 )alkyl, and R 5b is H.
22. The compound of claim 1 , wherein Het is selected from
23. The compound of claim 22 , wherein R 5a is selected from the group consisting of optionally substituted C 1-3 alkyl, —C(O)OH, C 3 -C 6 cycloalkyl(C 1 -C 2 )alkyl and phenyl(C 1 -C 2 )alkyl, R 5b is H, each X is O, R 1a and R 1b are H, R e is H, R c is other than H, and R a is NHR 7a .
24. The compound of claim 23 , wherein R 7a is C 3 -C 7 cycloalkyl, or 4-7 membered cycloheteroalkylC 1 -C 4 alkyl.
25. The compound of claim 24 , wherein R 7a is cyclopentyl.
26. A compound selected from the group consisting of
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
27. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof and a pharmaceutically acceptable excipient.
28. A combination comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof and at least one additional therapeutic agent.
29. A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof and at least one additional therapeutic agent.
30. A method of treating cancer in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof and an immune checkpoint inhibitor.
31. A method of treating cancer in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
32. The method of claim 31 , wherein said cancer is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, a brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.