CD73 inhibitors

1. A compound of Formula (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof:

wherein:

A is —O—;

Q 1 is N and Q 2 is N;

Z is —NR 1 R 2 ;

R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ;

or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ;

R 3 is halogen;

R 4 and R 7 are —OH;

R 5 and R 6 are hydrogen;

X 1 is a bond;

Y 1 is —S(═O) 2 —;

Y 2 is —(CR 45 R 46 ) v2 —;

R 45 and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

v2 is 1-3;

R 15a is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ;

R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ;

or R 16a and R 17a are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogens, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 , wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ;

or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ;

each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl;

each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl;

each w is independently 1-4;

each R 30a , R 30b , R 30g , R 30h , R 30k , and R 30l , are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 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, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ;

each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 or C 1 -C 6 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alky(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 30a .

3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is cycloalkyl, C 1 -C 6 alkyl(aryl), or C 1 -C 6 alkyl(cycloalkyl); wherein the alkyl, cycloalkyl, and aryl is optionally substituted with one, two, or three R 30a and R 2 is hydrogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of Formula (IIa) has the stereochemistry

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, selected from:

6. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, selected from:

9. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, selected from:

10. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically, acceptable salt or stereoisomer thereof, and one or more antitumor immunotherapy agents.

13. The method of claim 12 , wherein the one or more antitumor immunotherapy agents are selected from one or more checkpoint inhibitors, cancer vaccines, oncolytic viruses, cytokines, and CAR-T cells.

14. The method of claim 13 , wherein the one or more checkpoint inhibitors are selected from anti-PD1 inhibitors and anti-PD-L1 inhibitors.

15. The method of claim 12 , wherein the cancer in the subject is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, or prostate cancer.

16. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 5 , or a pharmaceutically acceptable salt thereof, and one or more antitumor immunotherapy agents.

17. The method of claim 16 , wherein the one or more antitumor immunotherapy agents are selected from one or more checkpoint inhibitors, cancer vaccines, oncolytic viruses, cytokines, and CAR-T cells.

18. The method of claim 17 , wherein the one or more checkpoint inhibitors are selected from anti--PD1 inhibitors and anti-PD-L1 inhibitors.

19. The method of claim 16 , wherein the cancer in the subject is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, or prostate cancer.