CD73 inhibitors
Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
1. A method of treating cancer in a subject, wherein the cancer is selected from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, lymphoma, leukemia, and multiple myeloma, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
Q 1 is CW;
Q 2 is N and Q 3 is N;
W is hydrogen;
R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 1a ;
each R 1a is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, or C 1 -C 6 hydroxyalkyl;
R 3 is hydrogen, halogen, —CN, OR b , SR b , C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 1 -C 6 hydroxyalkyl; wherein the alkyl and alkynyl is independently optionally substituted with one, two, or three R 3a ;
each R 3a is halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 hydroxyalkyl, or cycloalkyl;
R 4 and R 5 are —OR b ;
R 6 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or heterocycloalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a ;
each R 6a is —OR 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, deuterium, or C 1 -C 6 alkyl;
X is —O—;
Ring A is heterocycloalkyl or heteroaryl;
each R A is independently halogen, —CN, —OR b , —SR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl;
n is 0, 1, 2, 3, or 4;
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
R 21 and R 22 are independently hydrogen or C 1 -C 20 alkyl; and
each R b is independently hydrogen or C 1 -C 6 alkyl.
2. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3 is halogen, C 2 -C 6 alkynyl, or C 1 -C 6 hydroxyalkyl; wherein each alkyl and alkynyl is independently optionally substituted with one, two, or three R 3a .
3. The method of claim 2 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3 is halogen.
4. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 1a .
5. The method of claim 4 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 1a .
6. The method of claim 5 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 1a .
7. The method of claim 6 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is cycloalkyl.
8. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 1a is independently halogen, —CN, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl.
9. The method of claim 8 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 1a is independently halogen or C 1 -C 6 alkyl.
10. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is hydrogen or C 1 -C 6 alkyl.
11. The method of claim 10 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is hydrogen.
12. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 7 , R 8 , R 9 , and R 10 are independently hydrogen or C 1 -C 6 alkyl.
13. The method of claim 12 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 7 , R 8 , R 9 , and R 10 are hydrogen.
14. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring A is heteroaryl.
15. The method of claim 14 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, n is 0.
16. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or heterocycloalkyl; wherein the alkyl and heterocycloalkyl is independently optionally substituted with one, two, or three R 6a .
17. The method of claim 16 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a .
18. The method of claim 17 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a .
19. The method of claim 18 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is C 1 -C 6 hydroxyalkyl or C 1 -C 6 heteroalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a .
20. The method of claim 17 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is hydrogen, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; wherein the alkyl is independently optionally substituted with one, two, or three R 6a .
21. The method of claim 20 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 is C 1 -C 6 hydroxyalkyl.
22. The method of claim 1 , wherein in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 21 and R 22 are hydrogen.
23. The method of claim 1 , wherein the cancer is leukemia.
24. The method of claim 23 , wherein the leukemia is acute lymphocytic leukemia, chronic lymphocytic leukemia, myelocytic leukemia, refractory anemia, preleukemia, chronic myelomonocytic leukemia (CMML), or hairy cell leukemia.
25. The method of claim 1 , wherein the cancer is lymphoma.
26. The method of claim 25 , wherein the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.
27. The method of claim 1 , wherein the cancer is multiple myeloma.
28. The method of claim 27 , wherein the multiple myeloma is smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, or solitary plasmacytoma.
29. The method of claim 28 wherein the multiple myeloma is smoldering multiple myeloma.
30. The method of claim 28 , wherein the multiple myeloma is non-secretory, myeloma.
31. The method of claim 28 , wherein the multiple myeloma is osteosclerotic myeloma.
32. The method of claim 28 , wherein the multiple myeloma is plasma cell leukemia.
33. The method of claim 28 , wherein the multiple myeloma is solitary plasmacytoma.