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1. WO2020210451 - DEGRADERS OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 (FGFR2)

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

What is claimed is:

1 A bispecific compound having a structure represented by formula:


wherein the targeting ligand represents a moiety that binds fibroblast growth factor receptor 2 (FGFR2), the degron represents a moiety that binds an E3 ubiquitin ligase, and the linker represents a moiety that covalently connects the degron and the targeting ligand, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The bispecific compound of claim 1, which is represented by the formula (1-1):

wherein

R.3 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted amido, carboxyl, acrylamide, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and

m is an integer 0-4.

3. The compound of claim 2, wherein Rv is independently methyl, chloro, or methoxy.

4. The compound of claim 2, wherein m is 0.

5. The compound of claim 2, wherein m is 2.

6. The compound of claim 2, wherein m is 4.

7. The bispecific compound of claim 2, which is represented by formula I- la, I-lb, I-lc, I-ld, or I-le:


or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The bispecific compound of claim 1, which is represented by the formula (1-2):

wherein:

R1 is H or optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted amido, carboxyl, acrylamide, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; and

n is an integer 0-4;

or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The bispecific compound of claim 8, which is represented by the formula (I-2a):

pharmaceutically acceptable salt or stereoisomer thereof.

10. The bispecific compound of claim 1, which is represented by the formula (I-3a) or (I-3b):

pharmaceutically acceptable salt or stereoisomer thereof.

11. The bispecific compound of claim 1, which is represented by the formula (I-4):


or a pharmaceutically acceptable salt or stereoisomer thereof.

12. The bispecific compound of claim 1, wherein the linker is an alkylene chain or a bivalent alkylene chain, either of which may be interrupted by, and/or terminate at either or both termini in at least one of–O–,–S–,–N(R')–,–CºC–,–C(O)–,–C(O)O–,–OC(O)–,– OC(O)O–, –C(NOR')–, –C(O)N(R')–, –C(O)N(R')C(O)–, –C(O)N(R')C(O)N(R')–, – N(R')C(O)–,–N(R')C(O)N(R')–,–N(R')C(O)O–,–OC(O)N(R')–,–C(NR')–,–N(R')C(NR')–,– C(NR')N(R')–,–N(R')C(NR')N(R')–,–OB(Me)O–,–S(O)2–,–OS(O)–,–S(O)O–,–S(O)–,– OS(O)2–, –S(O)2O–, –N(R')S(O)2–, –S(O)2N(R')–, –N(R')S(O)–, –S(O)N(R')–, – N(R')S(O)2N(R')–,–N(R')S(O)N(R')–, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

13. The bispecific compound of claim 12, wherein the linker is an alkylene chain having 1-

10 alkylene units and interrupted by or terminating i

14. The bispecific compound of claim 1, wherein the linker is a polyethylene glycol chain which may terminate at either or both termini in at least one of –S–,–N(R')–,–CºC–,–C(O)– , –C(O)O–, –OC(O)–, –OC(O)O–, –C(NOR')–, –C(O)N(R')–, –C(O)N(R')C(O)–, – C(O)N(R')C(O)N(R')–,–N(R')C(O)–,–N(R')C(O)N(R')–,–N(R')C(O)O–,–OC(O)N(R')–,– C(NR')–,–N(R')C(NR')–,–C(NR')N(R')–,–N(R')C(NR')N(R')–,–OB(Me)O–,–S(O)2–,–

OS(O)–,–S(O)O–,–S(O)–,–OS(O)2–,–S(O)2O–,–N(R')S(O)2–,–S(O)2N(R')–,–N(R')S(O)– ,–S(O)N(R')–,–N(R')S(O)2N(R')–,–N(R')S(O)N(R')–, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R' is H or C1-C6 alkyl, wherein the one or both terminating groups may be the same or different.

15. The bispecific compound of claim 14, wherein the linker is a polyethylene glycol linker

having 2-8 PEG units and terminating

16. The bispecific compound of claim 1, which is represented by any one of the following structures:


or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The bispecific compound of any one of claims 1-16, wherein the degron binds cereblon.

18. The bispecific compound of claim 17, wherein the degron is represented by the formula D1-a or D1-b:


wherein

Y is NH, NMe, or O; and

Z is NH, O, or Cº.

19. The bispecific compound of claim 18, which is represented by any one of the following structures:

wherein

Y is NH, NMe, or O; and

Z is NH, O, or Cº;

or a pharmaceutically acceptable salt, or stereoisomer thereof.

20. The bispecific compound of any one of claims 1-16, wherein the degron binds von Hippel-Landau (VHL).

21. The bispecific compound of claim 20, wherein the degron is represented by any one of the structures:


wherein Z is a cyclic group;


wherein Y’’ is a bond, CH2, NH, NMe, O, or S; or stereoisomer thereof.

22. The bispecific compound of claim 21, which is represented by any one of the following structures:

wherein Y’ is a bond, NH, O or CH2,

wherein Z is a cyclic

group,
or a pharmaceutically acceptable salt or stereoisomer thereof.

23. The bispecific compound of any one of claims 1-16, wherein the degron binds an inhibitor of apoptosis protein (IAP).

24. The bispecific compound of claim 23, wherein the degron is represented by any one of the structures:


or stereoisomer thereof.

25. The bispecific compound of claim 24, which is represented by any one of the following structures:

,


or a pharmaceutically acceptable salt or stereoisomer thereof.

26. The bispecific compound of claim 1, which is:


acceptable salt or stereoisomer thereof.

27. A pharmaceutical composition, comprising a therapeutically effective amount of the bispecific compound of claim 1, or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

28. The method of treating a disease or disorder that is characterized or mediated by aberrant activity of FGFR2, comprising administering to a subject in need thereof a therapeutically effective amount of the bispecific compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

29. The method of claim 28, wherein the disease or disorder is cancer.

30. The method of claim 29, wherein the cancer is liver cancer.

31. The method of claim 31 , wherein the cancer is biliary tract cancer (BTC).

32. The method of claim 32, wherein the BTC is intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC).