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 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, C 1 -C 6 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 hydroxyaikyl;
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 —S— or —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;
provided that the compound is not
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
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 compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is halogen.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
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 compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
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 compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is cycloalkyl optionally substituted with one, two, or three R 1a .
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is cycloalkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each R 1a is independently halogen, —CN, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
each R 1a is independently halogen or C 1 -C 6 alkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen or C 1 -C 6 alkyl.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
X is —O—.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 7 , R 8 , R 9 , and R 10 are independently hydrogen or C 1 -C 6 alkyl.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:
R 7 , R 8 , R 9 , and R 10 are hydrogen.
15. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein:
Ring A is heteroaryl.
16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
n is 0.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
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 .
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein:
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 .
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
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 .
20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein:
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 .
21. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:
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 .
22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is C 1 -C 6 hydroxyalkyl.
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 21 and R 22 are hydrogen.
24. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
25. A method of inhibiting, CD73 comprising contacting CD73 with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.