Inhibitors of fibroblast activation protein

1. A compound of formula (A):

a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein:

R is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or C 6 -C 14 aryl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6 -C 14 aryl of R are independently optionally substituted by R d ;

R M is hydrogen or optionally substituted C 1 -C 6 alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4,

wherein m+n is 1, 2, 3, or 4;

X is —C(═O)—, —O—, —CH(OH)—, —S—, —S(═O)—, or —S(═O) 2 —

Y is

 wherein:

the wavy line represents the point of attachment to the rest of the molecule,

s is 1, 2, 3, or 4,

R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, halogen, cyano, —OR 14 , —NR 15 R 16 , —SR 14 , —NO 2 , —C═NH(OR 14 ), —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 S(O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , or —P(O)(OR 15 )(OR 16 ), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6 -C 14 aryl of R 11 and R 12 are each independently optionally substituted by one or more of R L ;

each R 13 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —NR 15 R 16 , —NO 2 , —C═NH(OR 14 ), —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 S(O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , or —P(O)(OR 15 )(OR 16 ), wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6 -C 14 aryl of R 13 are each independently optionally substituted by one or more R L ;

each R 14 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 14 are independently optionally substituted by halogen, —OH, oxo, cyano, or C 1 -C 6 alkyl optionally substituted by halogen, —OH, or oxo;

R 15 and R 16 , independently of each other and independently at each occurrence, are hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 15 and R 16 are independently optionally substituted by halogen, —OH, oxo, cyano, or C 1 -C 6 alkyl, optionally substituted by halogen, —OH, or oxo,

or R 15 and R 16 are taken together with the atom to which they are attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, cyano, or C 1 -C 6 alkyl optionally substituted by halogen, —OH, or oxo;

R d , independently at each occurrence, is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —OR14, —NR 15 R 16 , cyano, or nitro; and

each R L is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 6 -C 14 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, —C(O)R 14 , —OC(O)R 14 , —C(O)OR 14 , —C(O)NR 15 R 16 , —NR 14 C(O)R 15 , —NR 14 C(O)OR 15 , —NR 14 C(O)NR 15 R 16 , —S(O)R 14 , —S(O) 2 R 14 , —NR 14 S(O)R 15 , —NR 14 (O) 2 R 15 , —S(O)NR 15 R 16 , —S(O) 2 NR 15 R 16 , —P(O)(OR 15 )(OR 16 ), —NR 15 R 16 , cyano, oxo, or nitro, wherein (1) the C 1 -C 6 alkoxy is optionally substituted by halogen, —OH, oxo, cyano, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl optionally substituted by halogen, —OH, or oxo, (2) the C 1 -C 6 alkyl is optionally substituted by 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl is further optionally substituted by C 1 -C 6 alkyl, (3) the 5- to 10-membered heteroaryl is optionally substituted by oxo, and (4) the C 3 -C 8 cycloalkenyl is optionally substituted by halogen, —OH, oxo, cyano, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.

2. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (I):

3. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (Ia):

4. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (Ib):

5. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (II):

6. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIa):

7. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIb):

8. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is of formula (IIc):

9. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X is —C(═O)—.

10. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R is hydrogen or C 1 -C 6 alkyl.

11. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 11 is hydrogen, halogen, or C 1 -C 6 alkyl.

12. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 12 is hydrogen, halogen, or C 1 -C 6 alkyl.

13. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein each R 13 is independently selected from the groups consisting of:

wherein t is 0, 1, 2, 3, 4, or 5; and the wavy line represents the point of attachment to the rest of the molecule.

14. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 1.

15. The compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 2.

16. A compound selected from the group consisting of

a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 1 and R 13 is C 6 -C 14 aryl optionally substituted by one R L .

18. The compound of claim 17 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 13 is phenyl optionally substituted by one R L .

19. The compound of claim 18 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 13 is phenyl substituted by halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.

20. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 1 and R 13 is 3- to 12-membered heterocyclyl optionally substituted by one R L .

21. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein s is 1 and R 13 is 5- to 10-membered heteroaryl optionally substituted by one R L .

22. The compound of claim 21 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the 5- to 10-membered heteroaryl is imidazolyl, pyrazolyl, isoxazolyl, furyl, pyridyl, pyranyl, tetrahydroquinolinyl, isoindolinyl, benzofuranyl, benzoxazine, benzothiazolyl, or benzimidazolyl.

23. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R M is C 1 -C 6 alkyl.

24. A compound having the structure of

or a pharmaceutically acceptable salt.

25. A compound having the structure of

or a pharmaceutically acceptable salt.

26. A compound having the structure of

or a pharmaceutically acceptable salt.

27. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

28. A method of inhibiting FAP in an individual comprising administering to the individual a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

29. A method of inhibiting FAP in a cell comprising administering or delivering to the cell a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

30. A method of inhibiting FAP in a tumor comprising administering or delivering to the tumor a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

31. A method of inhibiting FAP in plasma comprising administering or delivering to the plasma a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

32. A method of enhancing an immune response in an individual comprising administering (a) an immune checkpoint inhibitor and (b) a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

33. A method of increasing the level of FGF21 expression in an individual comprising administering to the individual a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

34. A method of treating a disease or disorder associated with FGF21 in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the disease or disorder is diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver diseases, non-alcoholic steatohepatitis or cardiovascular diseases.

35. The method of claim 34 , wherein the disease or disorder is diabetes or obesity.

36. The method of claim 35 , wherein the diabetes is type I or type II diabetes.

37. A method of inhibiting FAP for treating a disease or disorder in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the disease or disorder is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal carcinoma, or adenocarcinoma.